KR102032418B1 - Fused-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a conjugated pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating a disease related to bruton tyrosine kinase activity comprising the same as an active ingredient. Since the conjugated pyrimidine derivative according to the present invention has excellent ability to inhibit the activity of Bruton's tyrosine kinase or TMD80, it can be usefully used for preventing or treating diseases related to Bruton's tyrosine kinase activity, especially cancer or autoimmune diseases. .

Description

Conjugated pyrimidine derivatives, methods for preparing the same, and pharmaceutical compositions for the prevention or treatment of bruton tyrosine kinase activity-related diseases comprising the same as an active ingredient, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient}

The present invention relates to a conjugated pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating a disease related to bruton tyrosine kinase activity comprising the same as an active ingredient.

Cancer is a state in which cell death is not normally regulated by various changes in gene expression and non-growth growth of cells is caused. Cancer cells have abnormally dividing and differentiating properties. The cancer cells penetrate adjacent tissues, destroy the tissues and metastasize to other sites, causing death.

Cancer is known to occur in any tissue of the body and is caused by one factor or by various factors that work together. These factors include a wide variety of chemicals, environmental factors such as radiation, infectious diseases such as viral infections, and genetic factors.

Targeted therapy, known as the second generation of cancer treatment, is a novel form of inducing anticancer effects by inhibiting the growth and survival of specific tumor cells by selectively inhibiting proteins or genes essential for tumor growth and tumor survival. As an anticancer treatment of cancer cells, only cancer cells can be specifically killed as compared to chemocancer drugs, which are first-generation cancer therapies that directly attack conventional cancer cells and thus have a high possibility of attacking normal cells.

As the target therapeutic agent, imatinib (Gleevec), which is widely used in chronic myeloid leukaemia (CML), inhibits the activity of Bcr-Abl fusion protein, which is widely distributed in CML patients, thereby reducing CML. ).

In addition, EGFR inhibitors such as gefitinib or erlotinib have recently been described as EGFR mutations (L858R, exon19 deletion) in patients with non-small-cell lung carcinoma (NSCLC), pancreatic cancer, and glioblastoma. It has been reported to have a selective effect on tumors with high activity of EGFR. In addition, crizotinib, recently approved by the FDA, has been shown to selectively treat patients with lung cancer with the EML4-ALK fusion gene.

Conventional anticancer agents (TANs) used in traditional chemotherapy are designed to target the 'fast cell division' characteristics of tumor cells, so that not only tumor cells that undergo 'fast cell division' but also relatively fast cell division There was a problem of severe side effects by damaging normal cells (eg, hair follicle cells, gastrointestinal cells, bone marrow cells, germ cells) and the like.

Novel antineoplastics (NANs), on the other hand, act specifically on tumor cells, which are essential for the survival of tumor cells but do not act on normal cells, or are designed to target signaling agents that do not affect normal cells. In addition to very high selectivity, cancer cells also contain a variety of oncogenes or tumor suppressor genes, but tumor growth or carcinogenesis is often maintained by continuous activation of one or two signaling pathways. Considering the characteristics of oncogene addiction of tumor cells that proliferation can be inhibited by inactivating only one oncogene, tumor selectivity of a new concept anticancer agent targeting tumor-specific signaling substances is very good. appear.

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase and is located on chromosome Xq22. In addition, BTK is a Tec family kinase, in addition to BTK, TEC, ITK, and TXK fall into this category. It is rarely expressed in other tissues, and is a protein that does not exist at all in T cells, but only in B cells.

Recently, Bruton's tyrosine kinase, an important terminal enzyme in the B-cell antigen receptor signaling pathway, has emerged as a new target, and its downstream signaling proteins are important for normal B-cells to function as growth, differentiation and lymphocytes. It plays a role of signaling. Moreover, Bruton's tyrosine kinases are known to be involved in the initiation, survival, and progression of mature B-cell lymphoproliferative disorders. Thus, if therapeutic agents are developed that can modulate the signaling of Bruton's tyrosine kinase, carcinoma and broton kinases It is very likely to be developed as a therapeutic agent for various immune related diseases.

In particular, BTK plays an important role in the downstream signaling of growth factors, B-cell antigens, chemokine receptors and innate immune receptors, resulting in cell growth, survival, differentiation, pathogenesis, angiogenesis, and signaling. , A protein that is critically involved in various cellular activities such as antigen presentation, plays an important role in the signaling of B-cells such as immunity, inflammation, and anticancer, and therefore BTK inhibitors attack other tissues. Instead, it can target only B cell tumors with BTK activity, which has the advantage of minimizing side effects occurring in patients during cancer treatment.

In particular, leukemia targeted by BTK inhibitors is chronically activated by B cell receptor signaling (BCR signaling) in which BTK function is important. You can optionally target it.

Conventional therapies for the treatment of chronic lymphocytic leukemia (CLL) have increased survival in younger patients, but have serious side effects of myelosuppression and increased infection in older patients. CLL therapies are now being studied in the direction of targeted therapies.

Thus, targeted therapies that inhibit BTK can effectively treat a variety of carcinomas and diseases involved in immunity while minimizing side effects in patients.

Therefore, the present inventors are trying to develop a compound exhibiting an effect of inhibiting Bruton's tyrosine kinase, and the conjugated pyrimidine derivatives of the specific structure according to the present invention excellently inhibit the activity of Bruton's tyrosine kinase or TMD80, The present invention was completed by finding that it can be used as a prophylactic and therapeutic agent for diseases related to Bruton's tyrosine kinase activity.

Korean Patent KR 10-2016-0062103

It is an object of the present invention to provide conjugated pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing the conjugated pyrimidine derivative.

It is another object of the present invention to provide a pharmaceutical composition for preventing or treating a disease related to Bruton's tyrosine kinase activity containing the conjugated pyrimidine derivative, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention to provide a health functional food composition for the prevention or improvement of Bruton's tyrosine kinase activity-related diseases containing the conjugated pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

n is 0 or 1;

A is a single bond, -NH- or -O-;

D ¹ is CR ⁴ or N, wherein said R ⁴ is hydrogen or linear or branched C _{1- 5} alkyl;

D ² is CH or N;

D ³ is N or NH;

은 단일결합 또는 이중결합이고;

Is a single bond or a double bond;

R ¹ is unsubstituted or substituted C _6-10 aryl,

Wherein the substituted C _{6- 10} aryl, straight or branched C _{1- 5} alkyl; Acryloylamine; Unsubstituted C _{6- 10} aryl; Unsubstituted C _{6- 10} aryloxy; At least one member selected from the group consisting of 5 to 7 membered unsubstituted or substituted heterocycloalkyl or heterocycloalkenyl including at least one hetero atom selected from the group consisting of N, O and S; May be substituted with one or more substituents,

In this case, the substituted heterocycloalkyl and heterocycloalkyl alkenyl, linear or branched C _{1- 5} alkyl; And linear or branched C _{1- 5} alkyl-carbonyl; and 1 or more substituents selected from the group consisting of consisting of one or more optionally substituted,

R ² and R ³ are each independently hydrogen; Unsubstituted or substituted C _{6- 10} aryl; 5 to 7 membered unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S; Unsubstituted or substituted C _3-7 cycloalkyl; Or unsubstituted or substituted indolinyl;

Together with the N atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms comprising one or more heteroatoms selected from the group consisting of N, O and S,

Wherein the substituted C _{6- 10} aryl, substituted heterocycloalkyl, substituted C _{3- 7} cycloalkyl, and substituted indolinyl is -NH _2; Acryloyl; Acryloylamine; And N, O and one or more C _1- to _{5-alkyl-carbonyl} of from 5 to 7 atoms or an unsubstituted straight or branched chain containing one or more heteroatoms at least one selected from the group consisting of S-substituted heterocycloalkyl; One or more substituents selected from the group consisting of).

In addition, the present invention as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 4 (step 1); And

A method for preparing a compound represented by Chemical Formula 1 according to claim 1 comprising the step (step 2) of obtaining a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 2 obtained in Step 1 with the compound represented by Chemical Formula 5 to provide:

Scheme 1

(상기 반응식 1에서,
n, A, D^1, D^2, D^3, R^1, R^2, R³ 및

는 제1항의 화합물명에서 정의된 바와 같고;
X¹ 및 X²는 각각 독립적으로 동일 또는 상이한 할로겐이고; 및
L¹은 수소,

또는

이다).

(In Scheme 1,
n, A, D ^1, D ^2, D ^3, R ^1, R ^2, R ³ and

Is as defined in the compound name of claim 1;
X ¹ and X ² are each independently the same or different halogen; And
L ¹ is hydrogen,

or

to be).

delete

delete

delete

Furthermore, the present invention, as shown in Scheme 2 below,

Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 5 (step 1); And

A method for preparing a compound represented by Chemical Formula 1 according to claim 1 comprising the step (step 2) of obtaining a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 6 obtained in Step 1 with the compound represented by Chemical Formula 4; to provide:

Scheme 2

(상기 반응식 2에서,
n, A, D^1, D^2, D^3, R^1, R^2, R³ 및

는 제1항의 화합물명에서 정의된 바와 같고;
X¹ 및 X²는 각각 독립적으로 동일 또는 상이한 할로겐이고; 및

(In Scheme 2,
n, A, D ^1, D ^2, D ^3, R ^1, R ^2, R ³ and

Is as defined in the compound name of claim 1;
X ¹ and X ² are each independently the same or different halogen; And

또는

이다).L ¹ is hydrogen,

or

to be).

delete

delete

In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases associated with Bruton's tyrosine kinase activity containing the compound represented by Formula 1, its optical isomers or pharmaceutically acceptable salts thereof as an active ingredient.

Furthermore, the present invention provides a health functional food composition for preventing or ameliorating a disease associated with Bruton's tyrosine kinase activity containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

Since the conjugated pyrimidine derivative according to the present invention has excellent ability to inhibit the activity of Bruton's tyrosine kinase or TMD80, it can be usefully used for preventing or treating diseases related to Bruton's tyrosine kinase activity, especially cancer or autoimmune diseases. .

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

n is 0 or 1;

A is a single bond, -NH- or -O-;

D ¹ is CR ⁴ or N, wherein said R ⁴ is hydrogen or linear or branched C _{1- 5} alkyl;

D ² is CH or N;

D ³ is N or NH;

은 단일결합 또는 이중결합이고;

Is a single bond or a double bond;

R ¹ is a C _{6- 10} aryl unsubstituted or substituted,

Wherein the substituted C _{6- 10} aryl, straight or branched C _{1- 5} alkyl; Acryloylamine; Unsubstituted C _{6- 10} aryl; Unsubstituted C _{6- 10} aryloxy; At least one member selected from the group consisting of 5 to 7 membered unsubstituted or substituted heterocycloalkyl or heterocycloalkenyl including at least one hetero atom selected from the group consisting of N, O and S; May be substituted with one or more substituents,

In this case, the substituted heterocycloalkyl and heterocycloalkyl alkenyl, linear or branched C _{1- 5} alkyl; And linear or branched C _{1- 5} alkyl-carbonyl; and 1 or more substituents selected from the group consisting of consisting of one or more optionally substituted,

R ² and R ³ are each independently hydrogen; Unsubstituted or substituted C _{6- 10} aryl; 5 to 7 membered unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S; An unsubstituted or substituted C _{3- 7} cycloalkyl; Or unsubstituted or substituted indolinyl;

Together with the N atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms comprising one or more heteroatoms selected from the group consisting of N, O and S,

Wherein the substituted C _{6- 10} aryl, substituted heterocycloalkyl, substituted C _{3- 7} cycloalkyl, and substituted indolinyl is -NH _2; Acryloyl; Acryloylamine; And N, O and one or more C _1- to _{5-alkyl-carbonyl} of from 5 to 7 atoms or an unsubstituted straight or branched chain containing one or more heteroatoms at least one selected from the group consisting of S-substituted heterocycloalkyl; One or more substituents selected from the group consisting of may be substituted.

Preferably,

N is 0 or 1;

A is a single bond, -NH- or -O-;

D ¹ is CR ⁴ or N, wherein said R ⁴ is hydrogen or linear or branched C _{1- 3} alkyl;

D ² is CH or N;

D ³ is N or NH;

은 단일결합 또는 이중결합이고;

Is a single bond or a double bond;

R ¹ is unsubstituted or substituted phenyl,

Where the substituted phenyl, linear or branched C _{1- 5} alkyl; Acryloylamine; Unsubstituted phenyl; Unsubstituted phenyloxy; At least one member selected from the group consisting of 5 to 6 membered unsubstituted or substituted heterocycloalkyl or heterocycloalkenyl including at least one hetero atom selected from the group consisting of N, O and S; May be substituted with one or more substituents,

In this case, the substituted heterocycloalkyl and heterocycloalkyl alkenyl, linear or branched C _{1- 3} alkyl; And straight chain or C _{1- 3} alkyl-carbonyl in the side chain; and 1 or more substituents selected from the group consisting of consisting of one or more optionally substituted,

R ² and R ³ are each independently hydrogen; Unsubstituted or substituted phenyl; 5 to 6 membered unsubstituted or substituted heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Unsubstituted or substituted C _{3- 6} cycloalkyl; Or unsubstituted or substituted indolinyl;

Together with the N atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 5 to 6 atoms comprising one or more heteroatoms selected from the group consisting of N, O and S,

Where the substituted phenyl, substituted heterocycloalkyl, substituted C _{3- 6} cycloalkyl, and substituted indolinyl is -NH _2; Acryloyl; Acryloylamine; And N, O and one or more of a C _{1- 3} alkyl-carbonyl of from 5 to 6 atoms unsubstituted or straight or branched chain containing one or more heteroatoms at least one selected from the group consisting of S-substituted heterocycloalkyl; One or more substituents selected from the group consisting of may be substituted.

More preferably,

N is 0 or 1;

A is a single bond, -NH- or -O-;

D ¹ is CR ⁴ or N, wherein R ⁴ is hydrogen or methyl;

D ² is CH or N;

D ³ is N or NH;

은 단일결합 또는 이중결합이고;

Is a single bond or a double bond;

R ¹ is unsubstituted or substituted phenyl,

Wherein the substituted phenyl is methyl; Acryloylamine; Unsubstituted phenyl; Unsubstituted phenyloxy; And one or more substituents selected from the group consisting of unsubstituted or substituted morpholinyl, piperazinyl, piperidinyl or 1, 4, 5, 6-tetrahydro-1, 2, 4-triazinyl Can be substituted more than

At this time, the substituted morpholinyl, piperazinyl, piperidinyl and 1, 4, 5, 6-tetrahydro-1, 2, 4-triazinyl is one selected from the group consisting of methyl and acetyl. May be substituted with one or more substituents,

R ² and R ³ are each independently hydrogen; Unsubstituted or substituted phenyl; Or unsubstituted or substituted pyrrolidinyl or piperidinyl; Unsubstituted or substituted cyclohexyl; Or unsubstituted or substituted indolinyl;

Together with the N atoms to which they are attached may form an unsubstituted or substituted piperazinyl,

Wherein the substituted phenyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclohexyl and indolinyl are -NH ₂ ; Acryloyl; Acryloylamine; Morpholinyl; And piperazinyl substituted with acetyl; one or more substituents selected from the group consisting of

Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds:

<1> 1- (4- (4-((6- (p-tolylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) piperazin-1-yl ) Ethan-1-one;

<2> 1- (4- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) pipe Razin-1-yl) ethan-1-one;

<3> (R) -N- (1- (6- (4-morpholinophenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidin-3-yl ) Acrylamide;

<4> (S) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine-3- I) acrylamide;

<5> 1- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- Yl) propen-2-en-1-one;

<6> 1- (4-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Ferridin-1-yl) propen-2-en-1-one;

<7> 4 (R) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine- 3-yl) acrylamide;

<8> (S) -1- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine- 4-yl) amino) piperidin-1-yl) prope-2-en-1-one;

<9> 1- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- I) propan-1-one;

<10> (S) -1- (3-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) piperidin-1-yl) propen-2-en-1-one;

<11> 1- (4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidin-1-yl) prope -2-en-1-one;

<12> 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- Yl) propen-2-en-1-one;

<13> 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- Yl) propen-2-en-1-one;

<14> N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide;

<15> N-((1s, 4s) -4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) Cyclohexyl) acrylamide;

<16> (R) -1- (3-((6-([1, 1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) pyrrolidin-1-yl) propen-2-en-1-one;

<17> (R) -1- (3-((6-([1, 1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) pyrrolidin-1-yl) propen-2-en-1-one;

<18> (R) -1- (3-((6-((4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine -1-yl) propen-2-en-1-one;

<19> (R) -1- (3-((6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4- I) amino) pyrrolidin-1-yl) prope-2-en-1-one;

<20> N-((1s, 4s) -4-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4- One) amino) cyclohexyl) acrylamide;

<21> N- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

<22> N-((1s, 4s) -4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylic amides;

<23> N-((1s, 4s) -4-((6- (4-phenoxyphenoxy) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) Acrylamide;

<24> N-((1s, 4s) -4-((3-methyl-6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] Pyrimidin-4-yl) amino) cyclohexyl) acrylamide;

<25> (R) -1- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine-1- Yl) propen-2-en-1-one;

<26> N-((1s, 4s) -4-((6-([1, 1'-biphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidine-4 -Yl) amino) cyclohexyl) acrylamide;

<27> N-((1s, 4s) -4-((2-((4-morpholinophenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) Cyclohexyl) acrylamide;

N- (2-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

N ^4, N ⁶ -bis (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidine-4, 6-diamine;

N ^4- (3-aminophenyl) -N2- (4-morpholinophenyl) -7H-pyrrolo [2, 3-d] pyrimidine-2, 4-diamine;

N- (3-((4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) acrylamide;

N- (3-((2-((4-morpholinophenyl) amino) -9H-purin-6-yl) amino) phenyl) acrylamide;

N- (3-((2-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

N- (3-((4-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;

N ^2, N ⁴ -bis (4-morpholinophenyl) pyrido [2, 3-d] pyrimidine-2, 4-diamine;

<37> N- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -3-methyl-1H-pyrazolo [3,4-d] pyrimidine- 4-yl) amino) phenyl) acrylamide;

N- (3-((6-((4- (1-methyl-5, 6-dihydro-1, 2, 4-triazin-4 (1H) -yl) phenyl) amino) -1H -Pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

1- (6-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) Prope-2-en-1-one;

<40> 1- (6-((2-((4-morpholinophenyl) amino) pyrido [2, 3-d] pyrimidin-4-yl) amino) indolin-1-yl) prope -2-en-1-one;

N- (3-((6-((3-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

N- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;

<43> 1- (6-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) prope- 2-en-1-one;

<44> 1- (6-((3-methyl-6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl Prope-2-en-1-one;

<45> N- (3-((3-methyl-4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) Acrylamide; And

<46> N- (3-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) Acrylamide.

The compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and organic acids such as acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or by distillation under reduced pressure of the solvent and excess acid, followed by drying and crystallization in an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

In addition, the present invention as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 4 (step 1); And

A method for preparing a compound represented by Chemical Formula 1 according to claim 1 comprising the step (step 2) of obtaining a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 2 obtained in Step 1 with the compound represented by Chemical Formula 5 to provide.

Scheme 1

In Scheme 1,

는 제1항의 화학식 1에서 정의한 바와 같고;n, A, D ^1, D ^2, D ^3, R ^1, R ^2, R ³ and

Is as defined in formula 1 of claim 1;

X ¹ and X ² are each independently the same or different halogen; And

또는

이다.L ¹ is hydrogen

or

to be.

Hereinafter, the manufacturing method represented by the reaction scheme 1 according to the present invention will be described in detail.

In the preparation method represented by Scheme 1 according to the present invention, Step 1 is a step of preparing a compound represented by Formula 2 by reacting the compound represented by Formula 3 with the compound represented by Formula 4, specifically, It is a step of obtaining a compound represented by the formula (2) by reacting the halogen of the compound represented by the formula (3) and L ¹ of the compound represented by the formula (4).

Specifically, when L ¹ is hydrogen, the reaction may proceed in the presence of a base, the base is not particularly limited, pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-dia Organic bases such as xabicyclo [5.4.0] -7-undecene (DBU) and the like or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, barium hydroxide and the like can be used alone or in mixtures in equivalent or excess amounts. .

In addition, the solvent usable in the above reaction is not particularly limited, but ether-based solvents such as tetrahydrofuran, dioxane, dichloromethane, 1 and 2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene and xylene; Alcohol solvents such as methanol and ethanol; Dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, water, and the like, which may be used alone or in combination.

또는

일 경우, 금속 촉매 및 염기 조건하에 반응시킬 수 있다.L ¹ is

or

In this case, the reaction may be carried out under metal catalyst and basic conditions.

In this case, the boronic acid compound may be used by commercially available compounds, or prepared by a known method from the corresponding halide compound.

As the metal catalyst, a palladium catalyst may be used, and available palladium catalysts may include Pd / C, Pd (PPh ₃ ) _4, PdCl _2, Pd (OCOCH ₃ ) _2, Pd (pph ₃ ) ₂ Cl ₂ , and the like. have. Preferably, Pd (pph ₃ ) ₂ Cl ₂ may be used, but is not limited thereto.

The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), or sodium hydroxide, sodium carbonate, Inorganic bases such as potassium carbonate, cesium carbonate, barium hydroxide and the like may be used alone or in combination, equivalents or excess, but are not limited thereto.

Examples of the solvent usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1 and 2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene and xylene; Alcohol solvents such as methanol and ethanol; Dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, water, and the like, which may be used alone or in combination.

In the preparation method represented by Scheme 1 according to the present invention, Step 2 is a step of obtaining a compound represented by Formula 1 by reacting the compound represented by Formula 2 obtained in Step 1 with the compound represented by Formula 5 Specifically, a step of obtaining a compound represented by Chemical Formula 4 by amination reaction between the halogen of the compound represented by Chemical Formula 2 and the secondary amine of the compound represented by Chemical Formula 5.

Solvents usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1, 2-dimethoxyethane and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc. can be used individually or in mixture.

Furthermore, the present invention, as shown in Scheme 2 below,

Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 5 (step 1); And

A method for preparing a compound represented by Chemical Formula 1 according to claim 1 comprising the step (step 2) of obtaining a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 6 obtained in Step 1 with the compound represented by Chemical Formula 4; to provide.

Scheme 2

In Scheme 2,

는 제1항의 화학식 1에서 정의한 바와 같고;n, A, D ^1, D ^2, D ^3, R ^1, R ^2, R ³ and

Is as defined in formula 1 of claim 1;

X ¹ and X ² are each independently the same or different halogen; And

또는

이다.L ¹ is hydrogen

or

to be.

In Scheme 2, the detailed description of Step 1 is the same as Step 2 of Scheme 1,

The details of step 2 are the same as in step 1 of scheme 1.

Furthermore, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of Bruton's tyrosine kinase activity and related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the Bruton's tyrosine kinase activity and related diseases may include cancer, autoimmune diseases, and the like.

At this time, the cancer is hematologic cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastases cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, fibrous tumor and brain tumor Autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia and Sjogren It is any one selected from the group which consists of a syndrome.

As a result of evaluating Bruton's tyrosine kinase activity inhibitory ability and TMD80 activity inhibitory ability of the conjugated pyrimidine derivatives according to the present invention, the conjugated pyrimidine derivatives showed the activity of Bruton's tyrosine kinase with an IC ₅₀ value of 10 μM or less. Inhibit, and Examples 3, 5, 12, 14-21, 24, 27, 28, 30, 32, 33, 37-39, 41, 45, and 46 compounds had a lower IC ₅₀ of 0.05 μM or less, i.e., 50 nM or less. Values, indicating that they exhibit excellent Bruton's tyrosine kinase activity inhibitory activity, and in particular, Examples 14, 15, 19-21, 33, 37-39 and 41 compounds exhibited significantly less than 0.008 μM, ie 8 nM or less. It was confirmed that the IC ₅₀ value inhibits Bruton's tyrosine kinase activity (see Experimental Example 1 and Table 3).

In addition, the conjugated pyrimidine derivatives according to the present invention inhibit the activity of TMD80 with IC ₅₀ values of 10 μM or less, and the compounds of Examples 11, 21, 27, 28 and 46 are 0.05 μM or less, i.e., low IC of 50 nM or less. _It showed that ₅₀ value was shown and it showed the outstanding inhibitory ability of TMD80 activity (refer Experimental example 2 and Table 3).

Therefore, the conjugated pyrimidine derivatives according to the present invention have excellent ability to inhibit the activity of Bruton's tyrosine kinase or TMD80, and thus can be usefully used for preventing or treating diseases related to Bruton's tyrosine kinase activity, especially cancer or autoimmune diseases. Can be.

In the pharmaceutical composition according to the present invention, the compound represented by Formula 1, the optical isomer thereof or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, orally and parenterally, during clinical administration. Can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. which are commonly used.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the compound represented by Formula 1, the optical isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient may be parenterally administered, and parenteral administration may be performed by subcutaneous injection, intravenous injection, muscle By injection of an intramuscular or intrathoracic injection.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, and it is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

In addition, the dosage of the pharmaceutical composition comprising the compound represented by Formula 1, the optical isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient may be determined by the age, weight, sex, dosage form, It may vary depending on the state of health and the degree of disease, preferably in an amount of 0.01 to 200 mg / kg / day a certain time interval several times a day, preferably once to three times a day at the discretion of the doctor or pharmacist Can be administered in divided oral or parenteral routes.

Furthermore, the pharmaceutical composition comprising as an active ingredient a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the present invention may be used alone or for the prevention or treatment of bruton tyrosine kinase activity-related diseases. It can be used in combination with methods using surgery, hormonal therapy, chemotherapy and biological response modifiers.

The present invention also provides a health food composition for preventing or ameliorating Bruton's tyrosine kinase activity and related diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the Bruton's tyrosine kinase activity and related diseases may include cancer or autoimmune diseases.

At this time, the cancer is hematologic cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastases cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, fibrous tumor and brain tumor Autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia and Sjogren It is any one selected from the group which consists of a syndrome.

There is no particular limitation on the kind of food. Examples of foods to which the substance may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like includes all the health functional foods in the conventional sense.

The compound represented by Chemical Formula 1 according to the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). Generally, the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control purposes, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and manufactured flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by the formula (1) according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as manufactured flavors and natural flavors, colorants and neutralizers (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. In addition, the compound represented by the formula (1) of the present invention may contain a fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following Examples and Experimental Examples are only illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

Example 1 1- (4- (4-((6- (p-tolylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) piperazine-1 Preparation of Ethanol-1-one

Step 1: 1- (4- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) Preparation of amino) phenyl) piperazin-1-yl) ethan-1-one

4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (200 mg, 0.73 mmol) and 1- (4- (4- Aminophenyl) piperazin-1-yl) ethan-1-one (193 mg, 0.88 mmol) is dissolved in butanol (2 mL) and potassium carbonate (152 mg, 1.1 mmol) is added thereto. The reaction is stirred for 13 hours. When the reaction is completed, the solvent is removed by distillation under reduced pressure, dichloromethane and water are added, and the product is extracted into the organic layer. The organic layer was dried over magnesium sulfate, concentrated, and then purified by column chromatography. The product 1- (4- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3 , 4-d] pyrimidin-4-yl) amino) phenyl) piperazin-1-yl) ethan-1-one (340 mg, 88%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.22 (m, 3H), 6.92 (d, J = 6.5 Hz, 1H), 5.87 (brs, 1H), 4.02 (m, 1H) , 3.75 (m, 2H), 3.68 (m, 2H), 3.30 (m, 2H), 2.48 (m, 1H), 2.21 (s, 3H), 2.12 (s, 1H), 1.82 (m, 1H), 1.78-1.52 (t, 9H), 0.98 (m, 2H).

Step 2: 1- (4- (4-((1- (tetrahydro-2H-pyran-2-yl) -6- (p-tolylamino) -1H-pyrazolo [3,4-d] pyrimidine Preparation of -4-yl) amino) phenyl) piperazin-1-yl) ethan-1-one

1- (4- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyridine in a sealed tube) Midin-4-yl) amino) phenyl) piperazin-1-yl) ethan-1-one (30 mg, 0.065 mmol), toluidine (8 mg, 0.074 mmol), Pd ₂ dba ₃ (3 mg, 0.006 mmol) , X-phos (9 mg, 0.021 mmol) and potassium carbonate (18 mg, 0.13 mmol) were added to butanol (2 mL) and reacted at 90 ° C. for 15 hours. The reaction solution was extracted with ethyl acetate (20 mL) and water (5 mL), and the organic layer was dried over magnesium sulfate, filtered and concentrated. Tube chromatography 1- (4- (4-((1- (tetrahydro-2H-pyran-2-yl) -6- (p-tolylamino) -1H-pyrazolo [3,4-d] pyrid Midin-4-yl) amino) phenyl) piperazin-1-yl) ethan-1-one (30 mg, 88%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.56 (d, J = 4.9 Hz, 2H), 7.37 (m, 2H), 7.15 (d, J = 4.9 Hz, 2H), 6.95 (m, 4H), 5.80 (d, J = 5.1 Hz, 1H), 4.12 (m, 1H), 3.75 (m, 2H), 3.65 (m, 2H), 3.18 (m, 4H), 2.54 (m, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 1.94 (m, 5H), 1.65 (m, 1H).

Step 3: 1- (4- (4-((6- (p-tolylamino) -1H-pyrazolo [3,4-d]? Rimidin-4-yl) amino) phenyl) pyrrazine-1 Production of ethan-1-one

1- (4- (4-((1- (tetrahydro-2H-pyran-2-yl) -6- (p-tolylamino) -1H-pyrazolo [3,4-d] pyrimidine-4- I) amino) phenyl) piperazin-1-yl) ethane-1-one (30 mg, 0.057 mmol) is dissolved in 1, 4-dioxane (1 mL), and hydrochloric acid solution (4 N, 1,4) -Dioxane, 0.5 mL) was added. The reaction solution was stirred at room temperature for 15 minutes and distilled under reduced pressure to remove the solvent. Recrystallization gave the product (13 mg, 43%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.65 (d, J = 4.9 Hz, 2H), 7.37 (m, 2H), 7.15 (d, J = 4.9 Hz, 2H), 7.01 (m, 4H) , 3.62 (m, 4H), 3.12 (m, 4H), 2.26 (s, 3H), 2.04 (s, 3H).

Example 2 1- (4- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl Preparation of Piperazin-1-yl) ethan-1-one

Step 1: 1- (4- (4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4 Preparation of -d] pyrimidin-4-yl) amino) phenyll) piperazin-1-yl) ethan-1-one

1- (4- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrid in a sealed tube Midin-4-yl) amino) phenyl) piperazin-1-yl) ethan-1-one (30 mg, 0.065 mmol), 4-morpholinoaniline (8 mg, 0.074 mmol), Pd ₂ dba ₃ (3 mg, 0.006 mmol), X-phos (9mg, 0.021 mmol), potassium carbonate (18 mg, 0.13 mmol) was added to n-butanol (2 mL) and reacted at 90 ° C. for 15 hours. The reaction solution was extracted with ethyl acetate (20 mL) and water (5 mL), and the organic layer was dried over magnesium sulfate, filtered and concentrated. Tube chromatography 1- (4- (4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d] pyrimidin-4-yl) amino) phenyll) piperazin-1-yl) ethan-1-one (40 mg, 88%) was synthesized.

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.46 (d, J = 9 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 6.90-6.81 (m, 5H), 5.68 (d, J = 9.1 Hz, 1H), 3.85-3.53 (m, 5H), 3.50 (s, 2H), 3.20-3.00 (m, 5H), 2.45-2.41 (m, 2H), 2.10-1.95 (m, 2H), 1.80-1.65 (m, 6H), 1.55-1.48 (m, 2H), 0.67-0.63 (m, 3H).

Step 2: 1- (4- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) pipe Preparation of Razin-1-yl) ethan-1-one

1- (4- (4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Pyrimidin-4-yl) amino) phenyll) piperazin-1-yl) ethan-1-one (50 mg, 0.057 mmol) is dissolved in 1,4-dioxane (1 mL), and hydrochloric acid (4 N, 1,4-dioxane, 3 mL) was added. The reaction solution was stirred at room temperature for 15 minutes and distilled under reduced pressure to remove the solvent. Recrystallization gave the product (27 mg, 78%).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.72-7.69 (m, 2H), 7.51-7.50 (m, 2H), 7.30-7.25 (d, J = 15.1 Hz, 5H), 3.78 (s, 3H) , 3.55 (s, 3H), 3.41-3.27 (m, 11H), 3.17 (s, 2H), 2.08 (s, 3H): LCMS calculated for C ₂₇ H ₃₁ N ₉ O ₂ = 513.26, found: 513.59.

Example 3 (R) -N- (1- (6- (4-morpholinophenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine-3 Preparation of -yl) acrylamide

Step 1: t-butyl ((3R) -1- (6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl Preparation of Piperidin-3-yl) carbamate

t-butyl (S) -piperidin-3-ylcarbamate (81 mg, 0.41 mmol) and 4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [ 3,4-d] pyrimidine (100 mg, 0.37 mmol), calcium carbonate (112 mg, 0.81 mmol) was added to dimethylformamide (2 mL) and stirred for 6 hours. The resulting solvent was extracted with ethyl acetate (15 mL) and water (5 mL), and the organic layer was dried over magnesium sulfate, filtered and concentrated. The product was obtained by tube chromatography. (145 mg, 70%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (brs, 1H), 8.01 (s, 1H), 5.93 (d, J = 6.7 Hz, 1H), 4.62 (s, 1H), 4.48-4.21 (m, 2H), 4.14 (m, 1H), 3.81 (m, 2H), 3.42 (m, 1H), 2.51 (m, 1H), 2.18 (m, 2H), 1.82 (m, 2H), 1.79 (m, 2H ), 1.65 (m, 2H), 1.45 (s, 9H).

Step 2: t-butyl ((3R) -1- (6-((4-morpholinopetyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4 -d] pyrimidin-4-yl) piperidin-3-yl) carbamate

t-butyl ((3R) -1- (6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperi Din-3-yl) carbamate (48 mg, 0.11 mmol), 4-morpholinoaniline (19 mg, 0.11 mmol), Pd ₂ (dba) ₃ (6.3 mg, 0.011 mmol), X-Phos (14 mg, 0.03 mol), potassium carbonate (31 mg, 22 mml) was dissolved in t-butanol (1 mL) and reacted at 90 ° C. for 15 hours. The reaction solution was extracted with ethyl acetate (15 mL) and water (5 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The product was obtained by tube chromatography. (34 mg, 60%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.52 (d, J = 9 Hz, 2H), 6.90 (d, J = 6 Hz, 2H), 6.79 (s, 1H), 5.81 (d, J = 12 Hz, 1H), 4.16-4.11 (m, 2H), 3.89-3.86 (m, 3H), 3.15-3.10 (m, 4H), 1.68-1.56 (m, 4H), 1.47-1.25 (m, 9 H).

Step 3: of (R) -4- (3-aminopiperidin-1-yl) -N- (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-6-amine Produce

t-butyl ((3R) -1- (6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Pyrimidin-4-yl) piperidin-3-yl) carbamate (34 mg, 0.051 mmol) is dissolved in methanol (1 mL), and hydrochloric acid (4 N, 1,4-dioxane, 1 mL) Was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and recrystallized to obtain a product. (20 mg, 84%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 10.20 (s, 1H), 8.58 (s, 3H), 7.51 (s, 1H), 7.27 (s, 1H), 4.56 (s, 1H), 3.78 (s , 6H), 3.08 (s, 6H), 1.87 (s, 1H), 1.72-1.69 (m, 1H), 1.62-1.60 (m, 2H): LCMS calculated for C ₂₀ H ₂₆ N ₈ O = 394.22, found : 394.47.

Step 4: (R) -4- (3-aminopiperidin-1-yl) -N- (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-6-amine Manufacture

(R) -4- (3-aminopiperidin-1-yl) -N- (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidin-6-amine (12 mg, 0.03 mmol), acrylic acid (4.4 mg, 0.061 mmol), 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide (24 mg, 0.15 mmol), HOBt (21 mg, 0.15 mmol) and diisopropylethyl Amine (20 mg, 0.15 mmol) was added to dichloromethane. After the reaction was stirred for 15 hours, the reaction solution was extracted with ethyl acetate (15 mL) and water (5 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The product was obtained by tube chromatography. (3 mg, 23%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.48 (d, J = 6 Hz, 2H), 6.85 (d, J = 6 Hz, 2H), 6.75 (s, 1H), 6.35 (d, J = 6 Hz, 1 H), 6.08-5.89 (m, 2H), 5.60 (d, J = 6 Hz, 1H), 3.89-3.75 (m, 4H), 3.70-3.68 (m, 1H ), 3.06-3.00 (m, 4H); LCMS calculated for C ₂₃ H ₂₈ N ₈ O ₂ = 448.23, found: 448.52.

Example 4 (S) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine- Preparation of 3-yl) acrylamide

(S) -4- (3-aminopyridin-1-yl) -N- (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidine in dichloromethane (2 mL) -6-amine (12 mg, 0.030 mmol) is dissolved, acrylic acid (4.2 μL, 0.061 mmol), 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide (24 mg, 0.15 mmol), hydroxybenzo Triazole (21 mg, 0.15 mmol) and diisopropylethylamine (28 μL, 0.15 mmol) are added, followed by stirring at room temperature for 13 hours. After the completion of the reaction, dichloromethane and water were added, and the organic layer obtained by layer separation was dried over magnesium sulfate and concentrated. The resulting rough product was column chromatographed with 5% methanol / dichloromethane to afford the title compound. (3 mg, 23%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.48 (d, J = 6 Hz, 2H), 6.85 (d, J = 6 Hz, 2H), 6.75 (s, 1H), 6.35 (d, J = 6 Hz, 1H), 6.08-5.89 (m, 2H), 5.60 (d, J = 6 Hz, 1H), 3.89-3.75 (m, 4H), 3.70-3.68 (m, 1H) , 3.06-3.00 (m, 4H): LCMS calculated for C ₂₃ H ₂₈ N ₈ O ₂ = 448.23, found: 448.52.

Example 5 1- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine- Preparation of 1-yl) prope-2-en-1-one

Step 1: t-butyl 4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Preparation of Ferridine-1-carboxylate

4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (100 mg, in N, N-dimethylformamide (1 mL) 0.36 mmol), then tert-butyl 4-aminopiperidine-1-carboxylate (81 mg, 0.40 mmol), potassium carbonate (10 mg, 0.74 mmol) was added and stirred at room temperature for 13 hours. After the reaction was completed, the reaction was worked up with ethyl acetate (5 mL) and water (1 mL), the organic layer was dried over magnesium sulfate, and the obtained product was concentrated by column chromatography with 30% ethyl acetate / hexanes to obtain the title compound. . (110 mg, 69%)

¹ H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 5.93-5.81 (d, 1H), 5.80 (brs, 1H), 4.08 (q, 3H), 3.75 (t, 1H), 2.91 (t , 2H), 2.47 (q, 1H), 2.05 (d, 4H), 1.86 (d, 1H), 1.68 (t, 2H), 1.58 (d, 1H), 1.47 (s, 9H), 1.28-1.23 ( t, 1 H).

Step 2: t -butyl 4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Preparation of Pyrimidin-4-yl) amino) piperidine-1-carboxylate

t -butyl 4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4- in t - butanol (2 mL) I) amino) piperidine-1-carboxylate (110 mg, 0.25 mmol) is dissolved, 4-morpholinoaniline (45 mg, 0.25 mmol) and Pd ₂ (dba) ₃ (1.5 mg, 0.0025) mmol), X-Phos (3.2 mg, 0.0076 mmol), potassium carbonate (71 mg, 0.51 mmol) is added, charged with nitrogen and stirred at 90 ^° C. overnight. After the reaction was completed, the solution was cooled, the solvent was removed, the concentrate was treated with ethyl acetate and water, and the reaction was worked up. The ethyl acetate layer was dried over magnesium sulfate and concentrated, and the column was chromatographed with 5% methanol / dichloromethane. do. (95 mg, 66%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.73 to 7.52 (d, 2H), 6.87 (d, 2H), 5.76 (d, 1H), 4.08 (d, 4H), 3.86 ( s, 4H), 3.09 (s, 4H), 2.87 (t, 2H), 2.48 (q, 1H), 2.02 (q, 4H), 1.89 (d, 2H), 1.78 (s, 2H), 1.47 (s , 9H), 1.27 (t, 1 H).

Step 3: Preparation of N ^6- (4-morpholinophenyl) -N ^4- (piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine-4, 6-diamine

t-butyl 4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Hydrochloric acid (4M, 1,4-dioxane, 6 mL) was added to 4-yl) amino) piperidine-1-carboxylate (95 mg 0.16 mmol), and methanol (1 mL) was further added, Stir at room temperature for 15 minutes. When the reaction was completed, the solvent was removed and recrystallized with diethyl ether to obtain the target compound. (40 mg, 82%)

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.49 (s, 1H), 7.83-77.7 (q, 4H), 4.14 (s, 4H), 3.71 (s, 4H), 4.39 (t, 1H), 3.49-3.47 (m, 3H), 3.19 (t, 1H), 3.25-3.15 (t, 1H), 1.92-1.91 (q, 2H).

Step 4: 1- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- (1) Preparation of prope-2-en-1-one

N ^6- (4-morpholinophenyl) -N4- (piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine (66 mg, 0.16 mmol) Was dissolved in dichloromethane (1 mL), then acrylic acid (14 mg, 0.2 mmol), 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide (130 mg, 0.83 mmol), hydroxybenzotriazole ( 113 mg, 0.83 mmol) and diisopropylethylamine (110 mg, 0.83 mmol) are added, followed by stirring at room temperature for 13 hours. After the reaction is completed, the mixture is extracted with dichloromethane and water, the organic layer is dried over magnesium sulfate, concentrated and subjected to column chromatography with 5% methanol / dichloromethane. (2.7 mg, 5%)

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.27 (s, 1H), 7.38 to 7.35 (d, 2H), 7.08 to 7.05 (d, 2H), 6.41 to 6.35 (d, 1H), 6.19 to 6.10 (q, 1H), 5.90-5.86 (d, 1H), 4.41 (t, 2H), 3.82 (t, 3H), 3.16 (t, 3H), 2.81 (t, 2H), 2.17-1.98 (m, 2H ), 1.52-1.48 (m, 2H), 1.35-1.26 (m, 2H).

Example 6 1- (4-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino Preparation of Piperidin-1-yl) prope-2-en-1-one

Step 1: 1- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Ferridin-1-yl) prope-2-en-1-one

The target compound was obtained in the same manner as in Step 1 of Example 5. (74%): LCMS calculated for C ₁₈ H ₂₃ ClN ₆ O ₂ = 390.87, found: 391.07.

Step 2: t-butyl 4- (4-((4-((1-acryloylpiperidin-4-yl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyra Zolo [3,4-d] pyrimidin-6-yl) amino) phenyl) piperidine-1-carboxylate

The target compound was obtained in the same manner as described in Step 2 of Example 5. (13%)

¹ H-NMR (300 MHz, CDCl ₃ ) δ7.78 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.60 (m, 1H), 6.28 (d, J = 18.0 Hz, 1H), 5.78 (d, J = 12.0 Hz, 1H), 5.70 (d, J = 12.0 Hz, 1H), 5.42 (s, 1H), 4.68 (s, 1H), 4.32 (s, 1H), 4.07 (s, 3H), 3.75 (s, 2H), 3.59 (t , J = 3.0 Hz, 4H), 3.23 (s, 2H), 3.07 (t, J = 3.0 Hz, 4H), 2.88 (s, 2H), 2.56 (s, 2H), 2.15 (s, 4H), 2.04 (s, 1 H), 1.48 (s, 9 H).

Step 3: 1- (4-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Ferridin-1-yl) prope-2-en-1-one

Synthesis was carried out according to the method of step 3 carried out in Example 5. (100%)

LCMS calculated for C ₂₃ H ₂₉ N ₉ O = 447.54, found: 448.05

Example 7 4 (R) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperi Preparation of din-3-yl) acrylamide

Step 1: t-butyl (3S) -3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl Preparation of Amino) piperidine-1-carboxylate

The target compound was obtained by the method of Example 3-1. (80%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ8.00-7.95 (m, 1H), 6.60 (s, 1H), 5.90 (d, J = 9 Hz, 1H), 4.15-4.08 (m, 1H), 3.80-3.51 (m, 1H), 3.00 (s, 4H), 2.89 (s, 3H), 2.55-2.43 (m, 1H), 1.80-1.75 (m, 1H), 1.73-1.48 (m, 6H), 1.45 (s, 9 H)

Step 2: t-butyl (3S) -3-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d] pyrimidin-4-yl) amino) piperidine-1-carboxylate

The target compound was obtained (74%) by the method of Example 3-2.

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.54 (d, J = 9 Hz, 2H), 6.89 (d, J = 9 Hz, 2H), 5.77 (d, J = 9 Hz, 1H), 3.87-3.85 (m, 4H), 3.78-3.75 (m, 2H), 3.74-3.48 (m, 2H), 3.45-3.27 (m, 2H), 3.20-3.10 (m, 4H), 2.60-2.45 (m, 9 H).

Step ^{3: (S) -N 6 -} (4- morpholinophenyl) -N ⁴ - (piperidin-3-yl) -1H- pyrazolo [3,4-d] pyrimidine-4, 6- Preparation of Diamine

The target compound was obtained by the method of Example 3-3. (82%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.94 (s, 1H), 8.57 (s, 1H), 7.89 (d, J = 6 Hz, 2H), 7.80 (d, J = 6 Hz, 2H), 7.61 (s, 1H), 4.63 (s, 1H), 4.17 (s, 3H), 3.81-3.70 (m, 3H), 3.52-3.48 (m, 1H), 3.40-3.32 (m, 6H), 2.21- 2.23 (m, 1 H), 2.02-1.99 (m, 1 H), 1.85-1.83 (m, 1 H).

LCMS calculated for C ₁₉ H ₂₂ N ₁₀ = 394.22, found: 394.47

Step 4: (R) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine-3 Preparation of -yl) acrylamide

The target compound was obtained by the method of Example 3-4. (30%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ7.89 (s, 1H), 7.60-7.51 (m, 2H), 6.78 (d, J = 6.1 Hz, 2H), 6.48-6.45 (m, 1H), 6.23 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 15.1 Hz, 1H), 5.76 (d, J = 6.1 Hz, 1H ), 5, 45-5.47 (m, 1H), 4.20-4.18 (m, 1H), 4.02 (d, J = 12.1 Hz, 2H), 3.79 (d, J = 9.1 Hz, 4H), 3.02 (d, J = 9.1 Hz, 4H), 2.15-2.10 (m, 1H), 2.00-1.9 5 (m, 2H), 1.90-1.85 (m, 1H), 1.35 (s, 2H): LCMS calculated for C ₂₃ H ₂₈ N ₈ O ₂ = 448.23, found: 448.52.

Example 8 (S) -1- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrid Preparation of midin-4-yl) amino) piperidin-1-yl) prope-2-en-1-one

Example 3 The procedure of step 3 was carried out to obtain the target compound. (35%, 15 mg)

LCMS calculated for C ₂₅ H ₃₁ N ₉ O ₂ = 489.57, found: 489.93.

Example 9 1- (4-((6-((4-morpholinophenyl) amino) -1 H -pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine Preparation of -1-yl) propan-1-one

N ^6- (4-morpholinophenyl) -N ^4- (piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine (50 mg, 0.12 mmol ) Is dissolved in tetrahydrofuran (3 mL), diisopropylethylamine (82 mg, 0.63 mmol) is added and stirred at 0 ^° C. for 10 minutes. Then propionylchloride (14 mg, 0.15 mmol) is added and stirred for another 10 minutes. N, N-dimenylaminopyridine (18 mg, 0.15 mmol) was added, followed by stirring for 10 minutes, after reaction with ethyl acetate and water, the organic layer was dried over magnesium sulfate and concentrated. The resultant was subjected to column column chromatography to obtain the target compound. (3.7mg, 6.2%)

¹ H NMR (300 MHz, Acetone-d ₆ ) δ 7.80 (s, 1H), 7.58-7.72 (d, 2H), 6.98-6.91 (t, 2H), 4.56-4.50 (d, 1H), 4.38-4.34 (q, 1H), 4.03-3.97 (d, 1H), 3.79-3.75 (t, 4H), 3.08-3.05 (t, 4H), 3.18-3.13 (t, 1H), 2.70-2.72 (d, 2H) , 2.41-2.33 (q, 2H), 1.50-1.40 (m, 2H), 1.08-1.02 (t, 3H).

Example 10 (S) -1- (3-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) piperidin-1-yl) prope-2-en-1-one

The target compound was obtained in the same manner as in Example 9 (7 mg).

LCMS calculated for C ₂₃ H ₂₉ N ₉ O = 447.54, found: 448.05

Example 11 1- (4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidin-1-yl) Preparation of Prope-2-en-1-one

Step 1: Preparation of t-butyl (1-acryloylpiperidin-4-yl) carbamate

Dissolve t-butyl piperidin-4-yl carbamate (1 g, 5 mmol) in dichloromethane (20 mL), acrylic acid (1.8 g, 25 mmol), 1-ethyl-3- (3-dimethylaminopyridine Carbodiimide (EDCI, 4.8 g, 25 mmol), hydroxybenzotriazole (HOBt, 1.35 g, 25 mmol), diisopropylethylamine (3.1 g, 25 mmol) were added and then at room temperature for 14 hours. Stir. After completion of the reaction, dichloromethane and water are added, and the product is extracted into the organic layer. The organic layer was dried over magnesium sulfate and concentrated. The concentrate was column chromatographed with 30% ethyl acetate / hexanes to afford the title compound. (750 mg, 60%)

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.57 (dd, J = 10.2, 6.6 Hz, 1H), 6.26 (d, J = 9.9 Hz, 1H), 5.68 (d, J = 6.6 Hz, 1H), 4.54 (s, 2H), 3.94 (d, J = 7.8 Hz, 1H), 3.69 (s, 1H), 3.16 (t, J = 7.5 Hz, 1H), 2.83 (t, J = 7.5 Hz, 1H), 2.01 (m, 2H), 1.45 (s, 9H), 1.32 (s, 2H).

Step 2: Preparation of 1- (4-aminopiperidin-1-yl) prope-2-en-1-one

t-Butyl (1-acryloylpiperidin-4-yl) carbamate (750 mg, 2.95 mmol) was added to methanol (20 mL), which was added hydrochloric acid (4N, 1,4-dioxane, 20 mL). ) Was added. After stirring for 15 minutes at room temperature, the reaction was terminated, the solvent was distilled off under reduced pressure, and recrystallized with ether to obtain the target compound. (40 mg, 82%)

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 6.85-6.75 (q, 1H), 6.23-6.17 (d, 1H), 5.78-5.74 (d, 1H), 4.62 (d, 1H), 4.21-4.20 (d, 1H), 4.08-4.06 (d, 1H), 2.85-2.75 (m, 1H), 2.15-2.04 (q, 2H), 1.61-1.45 (q, 2H).

Step 3: 1- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Ferridin-1-yl) prope-2-en-1-one

4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (300 mg, 1.1 mmol) in dimethylformamide (1 mL) After dissolving, 1- (4-aminopiperidin-1-yl) prop-2-en-1-one (186 mg, 1.2 mmol), potassium carbonate (760 mg, 5.5 mmol) is added and stirred at room temperature overnight. After the reaction was completed, ethyl acetate and water were added, the product was extracted with an organic layer, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was subjected to column chromatography to give the target compound. (110 mg, 69%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 6.85-6.80 (q, 1H), 6.76-6.18 (d, 1H), 5.82-5.73 (q, 2H), 4.55 (d, 1H ), 4.40 (t, 1H), 4.13 (d, 1H), 4.00 (d, 1H), 3.74 (t, 1H), 2.87-2.85 (m, 3H), 2.42 (q, 1H), 2.12-2.08 ( m, 4H), 2.78 (m, 3H).

Step 4: 1- (4-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole [3,4-d] pyrimidine-4 Preparation of -yl) amino) piperidin-1-yl) prope-2-en-1-one

In 1,4-dioxane (1.5 mL) and water (0.5 mL) 1- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, 4-d] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one (18 mg, 0.046 mmol) with 1,4-dioxane (1.5 mL) Dissolve in water (0.5 mL), 4,4,5,5-tetramethyl-2- (4-phenoxyphenyl) -1,3,2-dioxaborolane (14 mg, 0.051 mmol), pd (dppf ) ₂ Cl ₂ (2 mg, 0.0023 mmol), potassium carbonate (13 mg, 0.092 mmol) was added, followed by sufficient nitrogen injection, followed by reaction at 90 ° C. for 13 hours. After the reaction was completed, the solution was cooled, ethyl acetate and water were added to extract the product into the organic layer. The organic layer was dried over magnesium sulfate, concentrated and column chromatography to obtain the target compound. (7 mg, 27%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.47 (d, 2H), 7.99 (s, 1H), 7.40 (s, 1H), 7.40-7.30 (t, 2H), 7.17-7.01 (m, 4H), 6.65-6.55 (t, 1H), 6.32-6.23 (d, 1H), 6.09-6.03 (d, 1H), 5.93-5.86 (m, 1H), 5.72-5.66 (d, 1H), 4.64-4.52 (d , 2H), 4.17-4.01 (m, 2H), 3.77 (t, 1H), 3.67 (s, 1H), 3.26 (t, 1H), 2.89 (t, 1H), 2.55 (t, 1H), 2.35- 2.06 (m, 4H), 1.98-1.92 (d, 1H), 1.84-1.76 (m, 3H).

Step 5: 1- (4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidin-1-yl) prope Preparation of 2-en-1-one

1- (4-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole [3,4-d] pyrimidin-4-yl) To amino) piperidin-1-yl) prop-2-en-1-one (7 mg, 0.013 mmol) is added hydrochloric acid (4 M, 1,4-dioxane, 1.5 mL) and methanol (0.3 mL) ) Was added. The reaction solution is stirred at room temperature for 15 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and recrystallized with ether to obtain the target compound. (5.1 mg, 82%)

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.57 (s, 1H), 8.27 (s, 2H), 7.41 (s, 2H), 7.37 (s, 1H), 7.14 (s, 4H), 6.78 ( t, 1H), 6.18 (d, 1H), 5.74 (d, 1H), 4.59 (d, 1H), 4.18 (d, 1H), 2.96 (t, 1H), 2.16 (m, 2H), 1.61 (t , 2H), 1.49 (d, 1H), 1.14 (t, 1H).

Example 12 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine- Preparation of 1-yl) prope-2-en-1-one

Step 1: t-butyl 3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Preparation of Ferridine-1-carboxylate

4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (100 mg, 0.36 mmol) in dimethylformamide (1 mL) After dissolving, t-butyl 3-aminopiperidine-1-carboxylate (81 mg, 0.40 mmol), potassium carbonate (138 mg, 0.81 mmol) is added and stirred at room temperature for 13 hours. After the reaction was completed, ethyl acetate and water were added to extract the product into an organic layer, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was subjected to column chromatography to give the target compound. (151 mg, 78%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.02-7.98 (m, 1H), 5.85 (d, J = 12.0 Hz, 1H), 4.40 (s, 1H), 3.85-3.80 (m, 1H), 3.90 ( s, 1H), 3.85 (s, 1H), 2.55-2.48 (m, 1H), 1.90-1.85 (m, 2H), 1.83-1.70 (m, 2H), 1.65-1.53 (m, 2H), 1.45 ( s, 9H).

Step 2: t-butyl 3-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-al) -1H-pyrazolo [3,4-d] Preparation of Pyrimidin-4-yl) amino) piperidine-1-carboxylate

t-butyl-3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine 1-carboxylate (50 mg, 0.11 mmol) is dissolved in t- butanol (2 mL), 4-morpholinoaniline (21 mg, 0.11 mmol) and Pd ₂ (dba) ₃ (7 mg, 0.011 mmol), XPhos (15 mg, 0.034 mmol), potassium carbonate (33 mg, 0.24 mmol) is added, charged with nitrogen and stirred at 90 ^° C. for 13 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent, and the concentrate was added to ethyl acetate and water to extract the product into the organic layer. The organic layer was dried over magnesium sulfate and concentrated to give a target compound by column chromatography. (42 mg, 64%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.34 (d, J = 15.0 Hz, 2H), 7.04 (d, J = 15.0 Hz, 2H), 5.50 (d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 3.90-3.85 (m, 6H), 3.25-3.17 (m, 6H), 2.65 (s, 2H), 2.10-2.08 (m, 2H), 1.93-1.85 ( m, 2H), 1.70-1.65 (m, 2H), 1.30 (s, 9H).

Step 3: Preparation of N ^6- (4-morpholinophenyl) -N ^4- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine

t-butyl-3-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine To 4--4-yl) amino) piperidine-1-carboxylate, hydrochloric acid (4M, 1,4-dioxane, 4 mL) is added, to methanol (1 mL) and stirred at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (32 mg, 78%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 10.2 (s. 1H), 10.0 (s, 1H), 9.19 (s, 2H), 8.64 (s, 1H), 7.46 (d, J = 9.0 Hz, 2H) , 7.14 (d, J = 9.0 Hz, 2H), 4.38 (s, 1H), 3.85 (s, 5H), 3.25 (s, 7H), 2.91 (s, 1H), 1.93-1.90 (m, 1H), 1.70-1.67 (m, 1 H): LCMS calculated for C ₂₀ H ₂₆ N ₈ O = 394.22, found: 394.4.

Step 3: 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- (1) Preparation of prope-2-en-1-one

N ^6- (4-morpholinophenyl) -N ^4- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine (50 mg, 0.13 mmol ) Is added to tetrahydrofuran (3 mL), diisopropylethylamine (117 μL, 0.63 mmol) is added and stirred at 0 ^° C. for 10 minutes. Thereafter, acetyl chloride (12 μL, 0.15 mmol) is added and stirred for another 10 minutes. N, N -methylaminopyridine (18 mg, 0.15 mmol) was added, followed by further stirring for 10 minutes, followed by reaction with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was subjected to column column chromatography to obtain the target compound. (8 mg, 14%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.33-8.30 (m, 1H), 7.41 (d , J = 15.1 Hz, 2H), 7.12 (d, J = 15.1 Hz, 2H), 6.85-6.80 (m , 2H), 6.26-6.23 (m, 1H), 6.02-5.90 (m, 1H), 5.80-5.78 (m, 1H), 5.55-5.50 (m, 1H), 4.18-4.16 (m, 1H), 4.05 -4.01 (m, 1H), 3.95-3.85 (m, 3H), 3.30-3.20 (m, 3H), 3.05 (s, 1H), 2.87 (s, 1H), 2.41 (s. 1H), 2.20-2.13 (m, 1H), 1.78-1.74 (m, 1H), 1.60-1.55 (m, 1H), 1.44-1.41 (m, 1H), 1.38 (s, 1H), 1.30 (s, 1H): LCMS calculated for C ₂₃ H ₂₈ N ₈ O ₂ = 448.24, found: 448.52.

Example 13 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine- Preparation of 1-yl) prope-2-en-1-one

1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidin-1-yl) pro Dissolve Phen-2-en-1-one (50 mg, 0.12 mmol) in tetrahydrofuran (3 mL), add diisopropylethylamine (86 μL, 0.63 mmol) and stir at 0 ^o C for 10 minutes. . Propionyl chloride (18 μL, 0.25 mmol) is added to the reaction mixture, which is then stirred for 10 minutes. N, N -dimethylaminopyridine (19 mg, 0.25 mmol) was added thereto, stirred for 10 minutes, and after reaction with ethyl acetate and water, the organic layer was dried over magnesium sulfate and concentrated. The concentrate was subjected to column column chromatography to obtain the target compound. (8 mg, 14%)

LCMS calculated for C ₂₃ H ₃₀ N ₈ O ₂ = 450.24, found: 450.98.

Example 14 N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylic Preparation of Amides

Step 1: Preparation of t-butyl (4-acrylicaminocyclohexyl) carbamate

To dichloromethane (6 mL) add t-butyl (4-aminocyclohexyl) carbamate (100 mg, 0.46 mmol), acrylic acid (48 μL, 0.69 mmol), 1-ethyl-3- (3-dimethylaminopyridine Carbodiimide (EDCI, 362 mg, 2.3 mmol), hydroxybenzotriazole (HOBt, 316 mg, 2.3 mmol), diisopropylethylamine (431 μL, 431 mmol) were added, followed by stirring at room temperature for 13 hours. do. After completion of the reaction, dichloromethane (5 mL) and water (2 mL) were added for extraction, and the organic layer was dried over magnesium sulfate and concentrated to give a column chromatography. (97 mg, 77%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.39 (d, J = 18.0 Hz, 1H), 6.16-6.06 (m, 1H), 5.88 (d, J = 12.0 Hz, 1H), 5.65-5.50 (m , 1H), 4.50-4.41 (m, 1H), 3.93 (s, 1H), 3.62 (s, 1H), 2.60-2.52 (m, 1H), 1.75-1.70 (m, 2H), 1.60-1.55 (m , 3H), 1.48 (s, 9H), 1.17 (s, 1H), 0.83-0.82 (m, 1H).

Step 2: Preparation of N- (4-aminocyclohexyl) acrylamide

Hydrochloric acid (4M, 1,4-dioxane, 20 mL) was added to t-butyl (4-t-butyl (4-acrylaminocyclohexyl) carbamate (97 mg 0.36 mmol), and methanol (2 mL) was added thereto. After dissolving, the mixture was stirred for 15 minutes at room temperature When the reaction was completed, the solvent was removed and recrystallized with ether to obtain the target compound (89 mg, 70%).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.39 (d, J = 18.0 Hz, 1H), 6.16-6.06 (m, 1H), 5.88 (d, J = 12.0 Hz, 1H), 5.65-5.50 (m , 1H), 4.50-4.41 (m, 1H), 3.93 (s, 1H), 3.62 (s, 1H), 2.60-2.52 (m, 1H), 1.75-1.70 (m, 2H), 1.60-1.55 (m , 3H), 1.17 (s, 2H), 0.83-0.82 (m, 1H).

Step 3: N- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclo Preparation of hexyl) acrylamide

4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (28 mg, in N, N -dimethylformamide (1 mL) 0.11 mmol), and then N- (4-aminohexyl) acrylamide (30 mg, 0.11 mmol), potassium carbonate (146 mg, 1.11 mmol) is added and stirred at room temperature for 13 hours. After completion of the reaction, dichloromethane (5 mL) and water (2 mL) were added for extraction, and the organic layer was dried over magnesium sulfate and concentrated to give a column chromatography. (68 mg, 44%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 6.00 (d, J = 9.1 Hz, 1H), 4,15-4.12 (m, 1H), 3.85-3.80 (m, 1H), 2.60-2.53 (m, 1H), 2.35-2.20 (m, 1H), 2.18-2.10 (m, 1H), 2.00-1.95 (m, 1H), 1.74-1.63 (m, 2H), 1.60-1.52 (m , 1H), 1.30-1.23 (m, 1H).

Step 4: N- (4-((6-((4-morpholino) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrid Preparation of midin-4-yl) amino) cyclohexyl) acrylamide

N- (4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4- in t- butanol (2 mL) I) amino) cyclohexyl) acrylamide (30 mg, 0.17 mmol) is dissolved, 4-morpholinoaniline (14 mg, 0.17 mmol) and Pd ₂ (dba) ₃ (4 mg, 0.017 mmol), XPhos (22 mg, 0.052 mmol), K ₂ CO ₃ (21 mg, 0.23 mmol) is added, charged with nitrogen and stirred at 90 ^° C. for 15 hours. After the reaction was completed, the reaction was treated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was chromatographed to give the target compound. (20 mg, 50%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.55 (d, J = 12.1 Hz, 2H), 6.89 (d, J = 12.1 Hz, 2H), 6.45-6.36 (m, 1H ), 6.15-6.07 (m, 1H), 5.80-5.76 (m, 2H), 5.58-5.50 (m, 1H), 4.50-4.45 (m, 1H), 4.15-4.06 (m, 2H), 3.85-3.75 (m, 3H), 3.15-3.10 (m, 3H), 2.58-2.52 (m, 1H), 2.25-2.00 (m, 6H), 1.80-1.78 (m, 1H), 1.75-1.55 (m, 4H) , 1.50-1.25 (m, 2 H).

Step 5: N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide Produce

N- (4-((6-((4-morpholino) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4- in MeOH (0.5 mL)) d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide is added, hydrochloric acid (4M, 1,4-dioxane solution, 4mL) is added thereto, and the mixture is stirred at room temperature for 15 minutes. Upon completion of the reaction, the solvent was removed and recrystallized with ether to obtain the target compound. (24 mg, 64%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.55 (d , J = 12.1 Hz, 2H), 6.89 (d, J = 12.1 Hz, 2H), 6.45-6.36 (m, 1H ), 6.15-6.07 (m, 1H), 5.58-5.50 (m, 1H), 4.50-4.45 (m, 1H), 4.15-4.06 (m, 2H), 3.85-3.75 (m, 3H), 3.15-3.10 (m, 3H), 2.25-2.00 (m, 6H), 1.50-1.25 (m, 2H): LCMS calculated for C ₂₄ H ₃₀ N ₈ O ₂ = 462.25, found: 462.54.

Example 15 N -((1s, 4s) -4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) Preparation of Amino) cyclohexyl) acrylamide

Step 1: Preparation of t-butyl ((1s, 4s) -4-acrylamidocyclohexyl) carbamate

To dichloromethane (6 mL) t-butyl ((1s, 4s) -4-aminocyclohexyl) carbamate (517 mg, 2.42 mmol) was added and acrylic acid (668 μL, 9.6 mmol), 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide (2.9 g, 19.3 mmol), hydroxybenzotriazole (2.6 g, 19.3 mmol), diisopropylethylamine (3.6 mL, 19.3 mmol) were added, followed by 14 at room temperature. Stir for hours. After the reaction was completed, the reaction was treated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was chromatographed to give the target compound. (175 mg, 30%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.39 (d, J = 18.1 Hz, 1H), 6.16-6.06 (m, 1H), 5.88 (d, J = 12.1 Hz, 1H), 5.65-5.50 (m , 1H), 4.50-4.41 (m, 1H), 3.93 (s, 1H), 3.62 (s, 1H), 2.60-2.52 (m, 1H), 1.75-1.70 (m, 2H), 1.60-1.55 (m , 3H), 1.48 (s, 9H), 1.17 (s, 1H), 0.83-0.82 (m, 1H).

Step 2: Preparation of N -((1s, 4s) -4-aminocyclohexyl) acrylamide

Hydrochloric acid (4M 1,4-dioxane solution, 20 mL) was added to t-butyl ((1s, 4s) -4-acrylamidocyclohexyl) carbamate (150 mg, 0.81 mmol), and methanol (2 mL) was added. Add and stir at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (150 mg, 70%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 6.39 (d, J = 18.0 Hz, 1H), 6.16-6.06 (m, 1H), 5.88 (d, J = 12.1 Hz, 1H), 5.65-5.50 (m, 1H), 4.50-4.41 (m, 1H), 3.93 (s, 1H), 3.62 (s, 1H), 2.60-2.52 (m, 1H), 1.75-1.70 (m, 2H), 1.60-1.55 (m, 3H), 1.17 (s, 2H), 0.83-0.82 (m, 1H).

Step 3: N-((1s, 4s) -4-((6-chloro-1- (tetrahydro-2H-p-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) cyclohexyl) acrylamide

4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (185 mg, in N, N -dimethylformamide (2 mL) 0.68 mmol) is added, N-((1s, 4s) -4-aminocyclohexyl) acrylamide (200 mg, 0.74 mmol) and potassium carbonate (935 mg, 6.7 mmol) are added and stirred at room temperature for 14 hours. . After the reaction was completed, the reaction was treated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was chromatographed to give the target compound. (100 mg, 33%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 6.34-6.28 (m, 1H), 6.13-6.10 (m, 1H), 5.95-5.91 (m, 1H), 5.68-5.65 ( m, 1H), 4.10-4.60 (m, 2H), 3.75-3.79 (m, 1H), 3.00-2.88 (m, 1H), 2.60-2.57 (m, 1H), 2.35-2.20 (m, 2H), 1.95-1.80 (m, 4H), 1.78-1.68 (m, 2H), 1.58 (s, 3H).

Step 4: N-((1s, 4s) -4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [ Preparation of 3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide

t- butanol (2 mL) in N-((1s, 4s) -4-((6-chloro-1- (tetrahydro-2H-p-2-yl) -1H-pyrazolo [3,4-d ] Pyrimidin-4-yl) amino) cyclohexyl) acrylamide (52 mg, 0.12 mmol) is dissolved, 4-morpholinoaniline (23 mg, 0.13 mmol) and Pd ₂ (dba) ₃ (8 mg, 0.012 mmol), X-Phos (17 mg, 0.038 mmol), potassium carbonate (37 mg, 0.26 mmol) is added, charged with nitrogen and stirred at 90 ^° C. for 14 hours. After the reaction was completed, the reaction was treated with ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The concentrate was chromatographed to give the target compound. (60 mg, 86%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.50 (d, J = 12.1 Hz, 2H), 7.15-6.90 (m, 2H), 6.48-6.35 (m, 2H), 6.30 -6.20 (m, 1H), 5.85-5.70 (m, 2H), 5.55-5.50 (d, J = 12.1 Hz, 1H), 4.12-4.00 (m, 1H), 3.87 (s, 3H), 3.78-3.75 (m, 1H), 3.17-3.10 (m, 3H), 2.65-2.60 (m, 1H), 2.28-2.20 (m, 1H), 1.85-1.60 (m, 10H), 1.38-1.25 (m, 4H) .

Step 5: N-((1s, 4s) -4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) Preparation of Cyclohexyl) acrylamide

N-((1s, 4s) -4-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H- in methanol (1 mL) Hydrochloric acid (4M, 1,4-dioxane, 4 mL) is added to pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide and stirred at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (34 mg, 87%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 10.19 (s, 1H), 9.50 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.49 (d, J = 3.1 Hz, 2H ), 7.14 (d, J = 3.1 Hz, 2H), 6.38-6.35 (m, 1H), 6.07 (d , J = 9.1 Hz, 1H), 5.57 (d, J = 9.1 Hz, 1H), 3.80-3.64 (m, 5H), 3.15-3.00 (m, 5H), 1.60 (s, 7H), 1.58-1.56 (m, 2H): LCMS calculated for C ₂₄ H ₃₀ N ₈ O ₂ = 462.25, found: 462.55.

Example 16 (R) -1- (3-((6-([1,1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) pyrrolidin-1-yl) prope-2-en-1-one

Step 1: N-((1s, 4s) -4-((6-((4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclo Preparation of hexyl) acrylamide

N-((1s, 4s) -4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) 4-phenoxyaniline (49 mg, 0.27 mmol), Pd ₂ (dba) ₃ (10) in a solution of amino) cyclohexyl) acrylamide (90 mg, 0.22 mmol) in 1,4-dioxane (3 mL) mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), cesium carbonate (217 mg, 0.67 mmol) was added. The reaction mixture was filled with argon for 10 minutes and stirred at 150 ^° C. for 10 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure to remove the solvent, and purified by hexane / ethyl acetate under a silica gel column to give a white solid N-((1s, 4s) -4-((6- ( (4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (32 mg, 27%, 0.054 mmol, 42%) was obtained. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.61-2.18 (m, 14H), 2.55-2.64 (m, 1H), 3.72-3.79 (m, 1H), 4.09-4.20 (m, 3H), 5.49 ( br, 1H), 5.61 (d, J = 11.1 Hz, 1H), 5.80 (d, J = 8.4 Hz, 1H), 6.05-6.14 (m, 1H), 6.26-6.31 (m, 1H), 6.98-7.09 (m, 6H), 7.29-7.35 (m, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.79 (s, 1H), 8.74 (br, 1H).

Step 2: (R) -1- (3-((6-([1,1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl Preparation of Amino) pyrrolidin-1-yl) propen-2-en-1-one

N-((1s, 4s) -4-((6-((4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylic Hydrochloric acid (4N, 1,4-dioxane, 1 mL) was added to a solution in which the amide was dissolved in methanol (1 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate, and then the title compound (25 mg, 86%, 0.049 mmol) was obtained as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ 1.52-1.91 (m, 9H), 3.57-3.73 (m, 1H), 3.96 (brs, 1H), 4.18 (brs, 1H), 5.65 (d, J = 9.9 Hz, 1H), 6.19-6.41 (m, 2H), 7.01-7.16 (m, 5H), 7.35-7.49 (m, 4H), 8.43 (s, 1H); LC / MS 470.03 [M + H &lt; + &gt;], 940.32 [2M + H &lt; + &gt;].

Example 17 (R) -1- (3-((6-([1,1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) pyrrolidin-1-yl) prope-2-en-1-one

Step 1: 1-((3R) -3-((6-([1, 1'-biphenyl] -4-ylamino) -1- (tetrahydro-2H-pyran-2-yl) -1H- Preparation of pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one

1-((3R) -3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) [1,1'-Biphenyl]-in a solution of pyrrolidin-1-yl) prope-2-en-1-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) 4-amine (27 mg, 0.16 mmol), Pd ₂ (dba) ₃ (6 mg, 0.007 mmol), Xphos (3 mg, 0.007 mmol), cesium carbonate (130 mg, 0.40 mmol) was added. The reaction mixture was removed with argon for 10 minutes and dissolved in a microwave reactor at 140 ^° C. for 20 minutes. After the reaction mixture was cooled to room temperature, water was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to obtain the target compound (42 mg, 63%, 0.082 mmol) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.59-2.63 (m, 10H), 3.56-3.88 (m, 5H), 4.13 (d , J = 11.4 Hz, 1H), 4.79-5.00 (m, 1H) , 5.59-5.68 (m, 1H), 5.83 (d, J = 9.3 Hz, 1H), 6.31-6.39 (m, 2H), 7.16-7.17 (m, 1H), 7.29-7.33 (m, 1H), 7.40 -7.45 (m, 2H), 7.56-7.62 (m, 4H) 7.76-7.80 (m, 2H), 7.99-8.09 (m, 1H); LC / MS 509.97 [M + H &lt; + &gt;].

Step 2: (R) -1- (3-((6-([1,1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl Preparation of Amino) pyrrolidin-1-yl) propen-2-en-1-one

1-((3R) -3-((6-([1,1'-biphenyl] -4-ylamino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [ 3,4-d] pyrimidin-4-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one (42 mg, 0.082 mmol) in a solution of methanol (1 mL) Hydrochloric acid (4N, ethyl ether solution, 1 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate to obtain the title compound (30 mg, 83%, 0.065 mmol) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ 2.16-2.44 (m, 2H), 3.60-4.18 (m, 4H), 4.60-4.89 (m, 1H), 5.69-6.24 (m, 1H), 6.27 -6.54 (m, 1H), 6.57-6.71 (m, 1H), 7.26-7.29 (m, 1H), 7.37-7.42 (m, 2H), 7.53-7.60 (m, 4H), 7.82 (d, J = 7.8 Hz, 2H), 7.94 (s, 1 H); LC / MS 425.93 [M + H &lt; + &gt;], 851.21 [2M + H &lt; + &gt;].

Example 18 (R) -1- (3-((6-((4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Preparation of Lolidin-1-yl) prope-2-en-1-one

Step 1: 1-((3R) -3-((6-((4-phenoxyphenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4 Preparation of -d] pyrimidin-4-yl) amino) pyrrolidin-1-yl) prope-2-en-1-one

1-((3R) -3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) 4-phenoxyaniline (29 mg, 0.16) in a solution of pyrrolidin-1-yl) prope-2-en-1-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) mmol), Pd ₂ (dba) ₃ (6 mg, 0.007 mmol), Xphos (3 mg, 0.007 mmol), cesium carbonate (130 mg, 0.40 mmol) was added. The reaction mixture was removed with argon for 10 minutes and dissolved in a microwave reactor at 140 ^° C. for 20 minutes. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent, and then purified by hexane / ethyl acetate under a silica gel column to give a white solid target compound. (45 mg, 65%, 0.086 mmol) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.57-2.34 (m, 9H), 2.56-2.63 (m, 1H), 3.55-3.86 (m, 5H), 4.09-4.13 (m, 1H), 4.75- 4.87 (m, 1H), 5.59-5.68 (m, 1H), 5.79 (d, J = 9.9 Hz, 1H), 6.29-6.38 (m, 2H), 6.99-7.02 (m, 4H), 7.06-7.11 ( m, 2H), 7.29-7.35 (m, 2H), 7.65-7.69 (m, 2H), 7.99-8.08 (m, 1H); LC / MS 525.96 [M + H &lt; + &gt;].

Step 2: (R) -1- (3-((6-((4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine Preparation of -1-yl) prope-2-en-1-one

1-((3R) -3-((6-((4-phenoxyphenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Hydrochloric acid solution (4 N, diethyl) in pyrimidin-4-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one (45 mg, 0.086 mmol) in methanol (1 mL) Ether, 1 mL) was added and stirred at room temperature for 20 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate, and then the title compound (28 mg, 78%, 0.059 mmol) was obtained as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ 2.16-2.42 (m, 2H), 3.63-4.00 (m, 1H), 4.76 (br, 1H), 5.72-5.79 (m, 1H), 6.24-6.32 (m, 1H), 6.49-6.65 (m, 1H), 7.01-7.16 (m, 5H), 7.35-7.49 (m, 4H), 8.38 (s, 1H); LC / MS 441.91 [M + H ⁺ ], 883.14 [2M + H ⁺ ].

Example 19 (R) -1- (3-((6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine- Preparation of 4-yl) amino) pyrrolidin-1-yl) prope-2-en-1-one

Step 1: 1-((3R) -3-((6-((4- (piperidin-1-yl) phenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H Preparation of pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidin-1-yl) prope-2-en-1-one

1-((3R) -3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) 4- (piperidin-1-yl) in a solution of pyrrolidin-1-yl) prope-2-en-1-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) Aniline (28 mg, 0.16 mmol), Pd ₂ (dba) ₃ (6 mg, 0.007 mmol), Xphos (3 mg, 0.007 mmol), cesium carbonate (130 mg, 0.40 mmol) was added. The reaction mixture was removed with oxygen for 10 minutes with argon and stirred at 140 ^° C. for 20 minutes using a microwave reactor. After the reaction mixture was cooled to room temperature, water was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by hexane / ethyl acetate under silica gel column to obtain white solid target compound. (31 mg, 46%, 0.060 mmol) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.51-2.24 (m, 15H), 2.98 (br, 5H), 3.45-3.54 (m, 4H), 3.56-3.69 (m, 2H), 3.89-3.99 ( m, 2H), 4.59-4.66 (m, 1H), 5.64-5.68 (m, 2H), 6.09-6.15 (m, 1H), 6.48-6.66 (m, 1H), 6.82 (d, J = 8.7 Hz, 2H), 7.50-7.70 (m, 2H), 7.91 (s, 1H), 8.04-8.07 (m, 1H), 8.95 (s, 1H); LC / MS 517.05 [M + H ⁺ ], 753.06 [2M + H ⁺ ].

Step 2: (R) -1- (3-((6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4- I) Preparation of amino) pyrrolidin-1-yl) prope-2-en-1-one

1-((3R) -3-((6-((4- (piperidin-1-yl) phenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo A solution of [3,4-d] pyrimidin-4-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one (31 mg, 0.060 mmol) in methanol (1 mL) 4N diethyl ether hydrochloride solution (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate and then white solid target compound. (25 mg, 93%, 0.053 mmol) was obtained.

¹ H-NMR (300 MHz, CD ₃ OD) δ 1.84-2.44 (m, 8H), 3.59-4.03 (m, 8H), 4.74 (brs, 1H), 5.77-5.81 (m, 1H), 6.28 (d , J = 16.5 Hz, 1H), 6.57-6.71 (m, 1H), 7.84 (brs, 4H), 8.49 (s, 1H); LC / MS 432.94 [M + H &lt; + &gt;], 865.19 [2M + H ⁺ ].

Example 20 N -((1s, 4s) -4-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine- Preparation of 4-yl) amino) cyclohexyl) acrylamide

Step 1: Preparation of 2-ethoxy-1, 1-diisocyanoprop-1-ene

To malonitrile (3 g, 45 mmol), 1, 1, 1-triethoxyethane (10 mL, 54 mmol) is added, acetic acid (2 mL) is added, followed by removal of ethanol at 90 ^° C. The reaction solution is adjusted to 140 ^° C. and stirred for 30 minutes. After the reaction was completed, the white solid was filtered to obtain the target compound. (2.9 g, 87%)

¹ H NMR (500 MHz, CDCl ₃ ) δ4.45 (q, J = 9.1 Hz, 2H), 2.45 (s, 3H), 1.42 (t, J = 9.1 Hz, 3H).

Step 2: Preparation of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile

Hydrazine monohydrate (720 μL, 14.6 mmol) was added to 2-ethoxy-1,1-diisoprope-1-ene (1 g, 7.3 mmol), ethanol (10 mL) was added at 0 ° C., and dissolved. , 90 minutes at 80 ℃. At the end of the reaction, the mixture was cooled, ethyl acetate and water were added, the product was extracted with organic zucchini, the organic layer was dried over anhydrous manganese, filtered and concentrated, and the concentrated solution was subjected to column chromatography to obtain a target compound. (920 mg, 92%)

¹ H NMR (500 MHz, CDCl ₃ ) δ2.22 (s, 3H).

Step 3: Preparation of 3-methyl-1H-pyrazolo [3,4-d] pyrimidine-4, 6-diol

5-amino-3-methyl-1H-pyrazole-4-carbonitrile (0.92 g, 7.5 mmol) was added 20% potassium hydroxide (4.5 ml) and 10 ml dimethylsulfoxide at 0 ^° C. and stirred for 12 hours. Let it be. Next, CS ₂ was slowly added at 0 ^° C., followed by stirring for 30 minutes. And the mixture is stirred for another hour at room temperature. Iodine methane is slowly added to the reaction solution for 30 minutes. After stirring for 2 hours at room temperature, the reaction is added to ice water, and the resulting solid is filtered off. (620 mg, 75%). Next, acetic acid (30 mL) and hydrogen peroxide (30%, 7 mL) are added, followed by stirring at 70 ° C. for 5 hours. The solvent was removed, water was added, and the produced white solid was filtered to obtain the target compound. (100 mg, 37%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 12.92 (s, 1H), 11.15 (s, 1H), 10.49 (s, 1H), 2.46 (d, J = 12.1 Hz, 3H).

Step 4: Preparation of 4,6-dichloro-3-methyl-pyrazolo [3,4-d] pyrimidine

3-Methyl-1H-pyrazolo [3,4-d] pyrimidine-4,6-diol (100 mg, 0.60 mmol) was added to POCl ₃ (10 mL) and PCl ₅ (417 mg, 2.0 mmol) was added. It was. The reaction solution is refluxed for 12 hours, and when the reaction is completed, the reaction is added to ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous forget-me-not, filtered and concentrated, and then the target compound was obtained by tube chromatography. (70 mg)

LCMS calculated for C ₆ H ₄ Cl ₂ N ₄ = 201.98, found: 202.34.

Step 5: Preparation of 4, 6-dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine

4,6-Dichloro-3-methyl-1H-pyrazolo [3,4-d] pyrimidine (70 mg, 0.34 mmol) was added to ethyl acetate (2 mL) and dihydropyran (0.2 mL, 2.3 mmol) And p-toluenesulfonic acid (3 mg) were added. Stir at 50 ° C. for 12 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (30 mg, 54%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 5.99-5.51 (d, J = 9.1 Hz, 1H), 5.88 (d, J = 9.1 Hz, 1H), 3.98-3.96 (m, 1H), 3.75-3.73 (m, 1H), 2.65 (s, 3H), 2.47-2.45 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.78 (m, 1H), 1.65-1.55 (m, 2H), 1.26 (s. 1H).

Step 6: Preparation of t-butyl ((1s, 4s) -4-acrylamidocyclohexyl) carbamate

Dissolve t-butyl ((1s, 4s) -4-aminocyclohexyl) carbamate (517 mg, 2.4 mmol) in dichloromethane (6 mL), acrylic acid (668 μL, 9.6 mmol), 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide (2.9 g, 19.3 mmol), hydroxybenzotriazole (2.6 g, 19.3 mmol), diisopropylethylamine (3.6 mL, 19.3 mmol) were added, followed by 13 at room temperature. Stir for hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (175 mg, 30%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.39 (d, J = 18.1 Hz, 1H), 6.16-6.06 (m, 1H), 5.87 (d, J = 9.1 Hz, 1H), 5.85-5.84 (m , 1H), 4.60-4.45 (m, 1H), 3.93 (s, 1H), 3.62 (s, 1H), 2.55-2.52 (m, 1H), 1.85-1.75 (m, 2H), 1.65-1.50 (m , 2H), 1.48 (s, 9H), 1.35-1.25 (m, 2H), 0.83-0.80 (m, 1H).

Step 7: Preparation of N-((1s, 4s) -4-aminocyclohexyl) acrylamide

Hydrochloric acid (4M in 1,4-dioxane, 20 mL) was added to t-butyl ((1s, 4s) -4-acrylamidocyclohexyl) carbamate (150 mg, 0.82 mmol) and methanol (2 mL) After adding and melting, the mixture is stirred at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (150 mg, 70%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.39 (d, J = 18.1 Hz, 1H), 6.16-6.06 (m, 1H), 5.88 (d, J = 12.1 Hz, 1H), 5.65-5.50 (m , 1H), 4.50-4.41 (m, 1H), 3.93 (s, 1H), 3.62 (s, 1H), 2.60-2.52 (m, 1H), 1.75-1.70 (m, 2H), 1.60-1.55 (m , 3H), 1.17 (s, 2H), 0.83-0.82 (m, 1H).

Step 8: N-((1s, 4s) -4-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Preparation of pyrimidin-4-yl) amino) cyclohexyl) acrylamide

4,6-dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (362 mg, 1.26 in dimethylformamide (6 mL) mmol), and then N-((1s, 4s) -4-aminocyclohexyl) acrylamide (234 mg, 1.39 mmol), potassium carbonate Add (1.7 mg, 12.6 mmol) and stir at room temperature for 13 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (30 mg, 6%)

¹ H-NMR (500 MHz, CDCl ₃ δ 6.35-6.34 (m, 1H), 6.10-6.05 (m, 1H), 5.90-5.81 (m, 1H), 5.70-5.57 (m, 2H), 4.36 (s, 1H), 3.80-3.73 (m, 2H), 2.59 (s, 2H), 2.50-2.44 (m, 1H), 2.16 (s, 3H), 1.90-1.85 (m, 2H), 1.80-1.65 (m, 6H), 1.54 (s, 4H) .

Step 9: N -((1s, 4s) -4-((3-methyl-6-((4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyra Preparation of zolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide

t- butanol (2 mL) in N-((1s, 4s) -4-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3 , 4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (25 mg, 0.059 mmol), and 4-morpholinoaniline (11 mg, 0.059 mmol) with Pd ₂ (dba) ₃ (4 mg, 0.006 mmol), XPhos (8 mg, 0.017 mmol), potassium carbonate (25 mg, 0.17 mmol) is added, charged with nitrogen and stirred at 90 ^° C. for 14 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (14 mg, 42%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.58 (d, J = 12.1 Hz, 2H), 6.95-6.91 (d, J = 12.1 Hz, 2H), 6.30-6.23 (m, 2H), 5.65-5.62 (m, 2H), 4.25-4.20 (m, 1H), 4.10-3.95 (m, 2H), 3.72-3.68 (m, 3H), 3.12-3.07 (m, 3H), 2.51 (s, 3H), 2.41 (s, 1H), 2.05-1.88 (m, 2H), 1.80-1.75 (m, 6H), 1.60-1.50 (m, 2H), 1.35-1.25 (m, 6H), 0.87-0.83 (m, 4H) .

Step 10: N-((1s, 4s) -4-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4- (1) Preparation of amino) cyclohexyl) acrylamide

N-((1s, 4s) -4-((3-methyl-6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo To [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (14 mg, 0.025 mmol) is added hydrochloric acid (4M, 1,4-dioxane, 4 mL) and methanol (1 mL ) Is added and dissolved, and the mixture is stirred at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (6 mg, 87%)

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.00 (s, 4H), 6.80-6.75 (m, 2H), 5.50 (d, J = 9.1 Hz, 1H), 4.50 (s, 1H), 4.44-4.30 (m, 4H), 4.28-4.25 (s, 1H), 4.00-3.90 (m, 5H), 3.55 (s, 1H), 2.98 (s, 3H), 2.80-1.98 (m, 7H): LCMS calculated for C ₂₅ H ₃₂ N ₈ O ₂ = 476.26, found: 476.57.

Example 21 N- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide Manufacture

Step 1: N- (3-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Preparation of pyrimidin-4-yl) amino) phenyl) acrylamide

N- (3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (50 mg, 0.13 mmol) in solution dissolved in 1,4-dioxane (2 mL) 4-morpholinoaniline (27 mg, 0.15 mmol), Pd ₂ (dba) ₃ (6 mg, 0.006 mmol), Xphos (3 mg, 0.006 mmol) and cesium carbonate (122 mg, 0.38 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 140 ^° C. for 20 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted twice with ethyl acetate. The extracted organic layer was dried over anhydrous manganese (Na ₂ SO ₄ ), filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to give a white solid target compound (21 mg, 31%, 0.039 mmol). Got.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.61-1.74 (m, 4H), 1.91-1.95 (m, 1H), 2.05-2.11 (m, 2H), 2.20-2.60 (m, 1H), 3.09- 3.13 (m, 4H), 3.77-3.88 (m, 5H), 4.11-4.14 (m, 1H), 5.72-5.83 (m, 2H), 6.24-6.28 (m, 1H), 6.43 (d, J = 6.8 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.16-7.23 (m, 2H) 7.47-7.55 (m, 5H), 7.94 (s, 1H); LC / MS 541.00 [M + H ⁺ ].

Step 2: Preparation of N- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

N- (3-((6-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Hydrochloric acid (4N, ethyl ether, 1 mL) was added to a solution of 4-yl) amino) phenyl) acrylamide (20 mg, 0.039 mmol) in methanol (1 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, and then washed with ethyl acetate to obtain a white solid target compound (11 mg, 61%, 0.022 mmol).

¹ H-NMR (300 MHz, CD ₃ OD) δ 3.67 (brs, 4H), 4.12-4.15 (m, 4H), 5.81 (dd, J = 9.8 Hz, 2.1 Hz, 1H) 6.35-6.54 (m, 2H ), 7.41-7.74 (m, 7H), 8.05 (s, 1 H), 8.57 (s, 1 H); LC / MS 456.95 [M + H ⁺ ], 913.25 [2M + H ⁺ ].

Example 22 N-((1s, 4s) -4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl Production of Acrylamide

Step 1: N-((1s, 4s) -4-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4- d] Preparation of pyrimidin-4-yl) amino) cyclohexyl) acrylamide

N-((1s, 4s) -4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) In a solution of amino) cyclohexyl) acrylamide (50 mg, 0.12 mmol) in 1,4-dioxane (2 mL), (4-phenoxyphenyl) boronic acid (32 mg, 0.15 mmol), PdCl ₂ (PPh ₃ ) _2. (6 mg, 0.006 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 130 ° C. for 15 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous forget-me-not (Na ₂ SO ₄ ), filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to give a white solid target compound (31 mg, 46%, 0.060 mmol). Got.

¹ H-NMR (300 MHz, CDCl 3) δ 1.64-2.18 (m, 14H), 2.59-2.63 (m, 1H), 3.79-3.86 (m, 1H), 4.07-4.16 (m, 2H), 4.40 (brs , 1H), 5.62 (d, J = 9.9 Hz, 1H), 5.75 (brs, 1H), 6.08-6.14 (m, 2H), 6.28 (d, J = 17.1 Hz, 1H), 7.06-7.17 (m, 5H), 7.34-7.39 (m, 2H), 7.44-7.69 (m, 2H), 7.94 (s, 1H), 8.47 (d, J = 8.7 Hz, 2H); LC / MS 538.98 [M + H ⁺ ].

Step 2: N-((1s, 4s) -4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylic Preparation of Amides

N-((1s, 4s) -4-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrid To a solution of midin-4-yl) amino) cyclohexyl) acrylamide (30 mg, 0.060 mmol) in methanol (1 mL) was added hydrochloric acid (4N, diethyl ether, 0.2 mL), followed by stirring at room temperature for 30 minutes. I was. The reaction mixture was distilled under reduced pressure to remove the solvent, and then washed with ethyl acetate to obtain a white solid target compound (22 mg, 81%, 0.045 mmol).

¹ H-NMR (300 MHz, CD ₃ OD) δ 1.93-2.02 (m, 8H), 4.01 (brs, 1H), 4.61 (brs, 1H), 5.61 (d, J = 10 Hz, 2.1 Hz, 1H) , 6.20-6.36 (m, 2H), 7.12-7.29 (m, 4H), 7.44-7.65 (m, 3H), 8.26 (d, J = 9.0 Hz, 1H), 8.69 (s, 1H); LC / MS 454.99 [M + H &lt; + &gt;], 909.27 [2M + H ^& lt ^{; +} & gt ^; ].

Example 23 N-((1s, 4s) -4-((6- (4-phenoxyphenoxy) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclo Preparation of hexyl) acrylamide

Step 1: N -((1s, 4s) -4-((6- (4-phenoxyphenoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4 -d] preparation of pyrimidin-4-yl) amino) cyclohexyl) acrylamide

N-((1s, 4s) -4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) In a solution of amino) cyclohexyl) acrylamide (50 mg, 0.12 mmol) in dimethylpramide (2 mL), 4-phenoxyphenol (34 mg, 0.19 mmol), copper (Cu, 9 mg, 0.15 mmol) Cesium carbonate (120 mg, 0.37 mmol) and ethylenediamine (catalyst amount) were added. The reaction mixture was degassed with argon for 10 minutes and stirred at 150 ^° C. for 15 minutes using a microwave reactor. After the reaction mixture was cooled to room temperature, water was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to obtain a white solid target compound (36 mg, 53%, 0.065 mmol).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.59-2.18 (m, 12H), 2.50-2.64 (m, 1H), 3.69-3.81 (m, 1H), 4.02-4.10 (m, 3H), 5.62 ( d , J = 9.9 Hz, 1H), 5.80-5.84 (m, 3H), 6.07-6.12 (m, 1H), 6.27 (d, J = 16.8 Hz, 1H), 6.89-7.08 (m, 4H), 7.10 -7.19 (m, 3H), 7.32-7.37 (m, 2H), 7.87 (s, 1H); LC / MS 555.04 [M + H ⁺ ].

Step 2: N-((1s, 4s) -4-((6- (4-phenoxyphenoxy) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) Preparation of Acrylamide

N -((1s, 4s) -4-((6- (4-phenoxyphenoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Hydrochloric acid (4N, diethyl ether, 0.2 mL) was added to a solution of pyrimidin-4-yl) amino) cyclohexyl) acrylamide (30 mg) in methanol (1 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate, and then the title compound (26 mg, 81%, 0.051 mmol) was obtained as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ 1.53-1.85 (m, 8H), 3.82 (brs, 1H), 3.93 (brs, 1H), 5.64 (dd , J = 9.9 Hz, 2.1 Hz, 1H) , 6.19-6.39 (m, 2H), 7.02-7.19 (m, 5H), 7.31-7.43 (m, 4H), 8.59 (s, 1H); LC / M S470.98 [M + H ⁺ ], 941.20 [2M + H ⁺ ].

Example 24 N-((1s, 4s) -4-((3-methyl-6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4 -d] preparation of pyrimidin-4-yl) amino) cyclohexyl) acrylamide

Step 1: N-((1s, 4s) -4-((3-methyl-6-((4- (piperidin-1-yl) phenyl) amino) -1- (tetrahydro-2H-pyran- Preparation of 2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide

t- butanol (2 mL) in N-((1s, 4s) -4-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3 , 4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (20 mg, 0.047 mmol) is dissolved and 4- (piperidin-1-yl) aniline (8 mg, 0.048 mmol), Pd ₂ (dba) ₃ (3 mg, 4.7 μmol), X-Phos (7 mg, 0.014 mmol), potassium carbonate (14 mg, 0.098 mmol) is added, charged with nitrogen and stirred at 90 ^° C. for 14 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (15 mg, 86%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.49 (d, J = 12.1 Hz, 2H), 6.90 (d, J = 12.1 Hz, 2H), 6.76 s, 1H), 6.31-6.28 (m, 2H), 5.70-5.60 (m, 3H), 4.80-4.75 (m, 7H), 4.30-4.10 (m, 4H), 3.63-3.43 (m, 3H), 2.50 (s, 3H), 0.79-0.65 (m, 5H ).

Step 2: N-((1s, 4s) -4-((3-methyl-6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] Production of pyrimidin-4-yl) amino) cyclohexyl) acrylamide

N-((1s, 4s) -4-((3-methyl-6-((4- (piperidin-1-yl) phenyl) amino) -1- (tetrahydro-2H-pyran-2-yl ) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (25 mg, 0.052 mmol) was added to methanol (1 mL), followed by hydrochloric acid (4 N, 1,4-dioxane, 4 mL) was added, followed by stirring at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (2 mg, 12%)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85-7.72 (m, 4H), 6.30-6.25 (m, 2H), 5.64 (d, J = 9.1 Hz, 1H), 3.75-3.65 (m, 6H), 3.60-3.55 (m, 4H), 3.06 (s, 3H), 2.72 (s, 1H), 2.28-2.05 (m, 3H), 1.95-1.75 (m, 3H), 1.55-1.35 (m, 3H), 1.22 (s, 4H), 0.86 (s, 1H): LCMS calculated for C ₂₆ H ₃₄ N ₈ O = 474.29, found: 474.60.

Example 25 (R) -1- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine- Preparation of 1-yl) prope-2-en-1-one

Step 1: 1-((3R) -3-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Preparation of pyrimidin-4-yl) amino) pyrrolidin-1-yl) prope-2-en-1-one

1-((3R) -3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) (4-phenoxyphenyl boronic acid (34) in a solution of pyrrolidin-1-yl) prop-2-en-1-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) mg, 0.16 mmol), sodium carbonate (42 mg, 0.39 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 110 ^° C. for 10 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to obtain a white solid target compound (30 mg, 45%, 0.058 mmol).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.60-2.63 (m, 9H), 3.64-3.96 (m, 5H), 4.12-4.16 (m, 1H), 4.96-5.17 (brs, 1H), 5.59- 5.69 (m, 1H), 6.07 (d, J = 9.9 Hz, 1H), 6.31-6.42 (m, 2H), 7.07-7.26 (m, 5H), 7.36-7.69 (m, 4H), 8.19-8.24 ( m, 1H), 8.50 (d, J = 8.7 Hz, 2H); LC / MS 510.98 [M + H ⁺ ].

Step 2: (R) -1- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine-1- (1) Preparation of prope-2-en-1-one

1-((3R) -3-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- 4-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one (30 mg) in a solution of methanol (1 mL) in hydrochloric acid (4N, diethyl ether solution, 0.2 mL) ) Was added and stirred at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate to obtain the title compound (21 mg, 78%, 0.045 mmol) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ 2.30-2.55 (m, 2H), 3.74-3.17 (m, 4H), 5.18-5.27 (m, 1H), 5.74-5.82 (m, 1H), 6.27 -6.34 (m, 1H), 6.57-6.72 (m, 1H), 7.12-7.29 (m, 5H), 7.44-7.49 (m, 2H), 8.30 (d, J = 8.7 Hz, 2H), 8.65 (s , 1H); LC / MS 426.88 [M + H ⁺ ], 854.12 [2M + H ⁺ ].

Example 26 N-((1s, 4s) -4-((6-([1, 1'-biphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidine Preparation of -4-yl) amino) cyclohexyl) acrylamide

Step 1: N-((1s, 4s) -4-((6-([1,1'-biphenyl] -4-ylamino) -1- (tetrahydro-2H-pyran-2-yl)- Preparation of 1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide

N-((1s, 4s) -4-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) [1,1'-biphenyl] -4-amine (25 mg, 0.15 mmol) in a solution of amino) cyclohexyl) acrylamide (50 mg, 0.12 mmol) in 1,4-dioxane (2 mL), Pd ₂ (dba) ₃ (6 mg, 0.006 mmol), Xphos (3 mg, 0.006 mmol), cesium carbonate (120 mg, 0.37 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 140 ^° C. for 20 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to obtain a white solid target compound (40 mg, 61%, 0.074 mmol).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.73-2.18 (m, 14H), 2.64 (brs, 1H), 3.60-3.82 (m, 1H), 5.60 (d , J = 10.2 Hz, 2H), 5.82 -5.93 (m, 2H), 6.04-6.14 (m, 1H), 6.28 (d, J = 16.8 Hz, 1H), 7.26-7.34 (m, 3H), 7.41-7.46 (m, 2H), 7.55-7.61 (m, 4H), 7.75 (d, J = 8.7 Hz, 1H), 7.82 (s, 1H); LC / MS 537.97 [M + H ⁺ ].

Step 2: N-((1s, 4s) -4-((6-([1,1'-biphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) cyclohexyl) acrylamide

N-((1s, 4s) -4-((6-([1,1'-biphenyl] -4-ylamino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyra Hydrochloric acid (4N, diethyl ether solution, 0.2 mL) was added to a solution of zolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (35 mg) in methanol (1 mL). It was added and stirred at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with ethyl acetate to obtain a white solid target compound (28 mg, 88%, 0.057 mmol).

¹ H-NMR (300 MHz, CD ₃ OD) δ 1.75-1.95 (m, 8H), 3.98 (brs, 1H), 34.2 (brs, 1H), 5.66 (d, J = 11.7 Hz, 1H), 6.23 ( d, J = 17.4 Hz, 1H), 7.32-7.37 (m, 1H), 7.43-7.48 (m, 2H), 7.61-7.72 (m, 6H), 8.48 (s, 1H); LC / MS 453.91 [M + H ⁺ ], 907.24 [2M + H ⁺ ].

Example 27 N-((1s, 4s) -4-((2-((4-morpholinophenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) Preparation of Amino) cyclohexyl) acrylamide

Step 1: Preparation of 7H-pyrrolo [2,3-d] pyrimidine-2,4-diol

To a solution of 6-aminopyrimidine-2,4-diol (2.0 g, 15.7 mmol) in water (20 mL) was added sodium acetate (1.29 g, 23.60 mmol) and heated to 80 ^° C. Chloroacetaldehyde was added to the reaction mixture, which was then stirred at 80 ^° C. for 4 hours. After cooling the reaction mixture to room temperature, the solid was filtered and washed with water to obtain a brown solid 7H-pyrrolo [2,3-d] pyrimidine-2,4-diol (1.60 g, 66%, 10.6 mmol).

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 4.39 (s, 1H), 6.18 (s, 2H), 10.09 (s, 2H); LC / MS 151.97 [M + H ⁺ ], 302.98 [2M + H ⁺ ].

Step 2: Preparation of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine-2,4-diol

In a solution of 7H-pyrrolo [2,3-d] pyrimidine-2,4-diol (1.0 g, 6.6 mmol) in POCl ₃ (4 mL, 43.0 mmol)), N, N-dimethylaniline (0.4 g, 3.3 mmol) was added. The reaction mixture was stirred at 180 ^° C. for 20 minutes. After the reaction mixture was cooled to room temperature, ice water was added to terminate the reaction. The resulting solid was filtered and purified using hexanes / EtOAc under a silica gel column to obtain the title compound (300 mg, 25%, 1.59 mmol) as a white solid. .

¹ H-NMR (300 MHz, DMSO- d ₆ ) 6.63 (d, J = 1.5 Hz, 1H), 7.70 (s, 1H), 12.76 (s, 1H); LC / MS 188.02 [M + H ⁺ ].

Step 3: Preparation of N-((1s, 4s) -4-((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide

Cis-1,4- in a solution of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine-2,4-diol (100 mg, 0.53 mmol) in dimethylformamide (2 mL) Cyclohexanediamine (73 mg, 0.64 mmol), K ₂ CO ₃ (220 mg, 1.59 mmol) was added. The reaction mixture was stirred at 80 ^° C. for 14 hours. The reaction mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent, followed by addition of chloroform: methanol (1: 1). The resulting solid was removed and the remaining solution was distilled under reduced pressure to obtain a solid (100 mg, 0.38 mmol) which was then used for the reaction. To a solution of the obtained solid (100 mg, 0.38 mmol) in dimethylformamide, acrylic acid (32 mg, 0.45 mmol), HATU (285 mg, 0.75 mmol) and triethylamine (0.16 mL, 1.13 mmol) were added thereto, and the mixture was stirred at room temperature. Stir for hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and then extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to obtain a white solid target compound (80 mg, 47%, 0.25 mmol).

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.61-1.98 (m, 8H), 3.79 (brs, 1H), 3.99 (brs, 1H), 5.54 (d , J = 9.6 Hz, 1H), 6.05 (d , J = 16.5 Hz, 1H), 6.28-6.65 (m, 1H), 6.65 (s, 1H), 7.05 (s, 1H), 7.54 (s, 1H), 7.94 (s, 1H), 11.62 ( s, 1 H); LC / MS 319.89 [M + H ⁺ ], 638.92 [2M + H ⁺ ].

Step 4: N-((1s, 4s) -4-((2-((4-morpholinophenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) Preparation of Cyclohexyl) acrylamide

N-((1s, 4s) -4-((2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide (40 mg, 0.13 mmol) 4-morpholinoaniline (27 mg, 0.15 mmol), Pd ₂ (dba) _{3 in} solution dissolved in t-butanol (2 mL) (6 mg, 0.006 mmol), Xphos (3 mg, 0.006 mmol), cesium carbonate (52 mg, 0.38 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 90 ^° C. for 16 hours. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted twice with ethyl acetate. The extracted organic layer was dried over Na ₂ SO ₄ , filtered, distilled under reduced pressure, solvent removed, and purified using hexane / EtOAc under silica gel column to obtain the target compound (15 mg, 26%, 0.030 mmol) as a yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.71-2.05 (m, 8H), 3.09 (brs, 4H), 3.86 (brs, 4H), 4.08-4.11 (m, 1H), 4.23 (brs, 1H) , 4.80-5.00 (m, 1H), 5.65 (d, J = 9.3 Hz, 1H), 6.12-6.18 (m, 2H), 6.28-6.33 (m, 1H), 6.49 (s, 1H), 6.71 (s , 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 9.41 (s, 1H); LC / MS 462.01 [M + H ⁺ ], 923.38 [2M + H ⁺ ].

Example 28 N- (2-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide Manufacture

Step ^1: N 1 - (6- chloro-l- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidin-4-yl) benzene-1,2- Preparation of Diamine

A solution of 4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (500 mg, 1.8 mmol) in ethanol (5 mL) To 1,2-phenylenediamine (247 mg, 2.19 mmol) and Et ₃ N (0.76 mL, 5.49 mmol) were added and stirred at room temperature for 30 minutes. The resulting solid was filtered, washed with ethanol to give a white solid target compound (580 mg, 92%, 1.68 mmol).

LC / MS 344.89 [M + H ⁺ ], 689.00 [2M + H ⁺ ].

Step 2: N- (2-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide Manufacture

N ¹ - (6- chloro-l- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidin-4-yl) benzene-1,2-diamine (250 mg, 0.73 mmol) and acrylic acid (63 mg, 0.87 mmol) in a solution of tetrahydrofuran (10 mL). HATU (550 mg, 1.45 mmol), triethylamine (0.25 mL, 1.81 mmol) were added at 0 ^° C. The reaction mixture was stirred at room temperature for 4 hours. Water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (200 mg, 69%, 0.501 mmol) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.63-2.11 (m, 5H), 2.49 (brs, 1H), 3.79-3.83 (m, 1H), 4.08-4.13 (m, 1H), 5.80 (d , J = 10.2 Hz, 1H), 5.92 (d , J = 9.9 Hz, 1H), 6.20-6.29 (m, 1H), 6.45 (d, J = 16.8 Hz, 1H), 7.18-7.26 (m, 2H), 7.42-7.44 (m, 2H), 8.40 (brs, 2H); LC / MS 398.95 [M + H ⁺ ], 997.07 [2M + H ⁺ ].

Step 3: Preparation of N- (2-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

N- (2-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (120 mg, 0.30 mmol) in hydrochloric acid (0.08 M, ethoxy ethanol, 3 mL, 10 mmol%) was stirred at 90 ^° C. for 16 h. After cooling the reaction mixture to room temperature, the resulting solid was filtered and washed with ethanol to obtain the target compound (70 mg, 47%, 0.14 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.21 (brs, 4H), 3.83 (brs, 4H), 5.70 (d, J = 10.2 Hz, 1H), 6.21 (d , J = 17.4 Hz, 1H ), 6.51-6.57 (m, 1H), 7.11 (brs, 2H), 7.24-7.39 (m, 4H), 7.59 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 6.9 Hz, 1H) , 8.60 (br, 1 H), 10.21 (brs, 1 H), 11.30 (brs, 1 H); LC / MS 456.99 [M + H ⁺ ].

Example 29 N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide Manufacture

Step ^1: N 1 - (6- chloro-l- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidin-4-yl) benzene-1,4- Preparation of Diamine

4,6-Dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (500 mg, 1.83 mmol) in ethanol (5 mL) To 1,4-phenylenediamine (296 mg, 2.75 mmol) and Et ₃ N (0.51 mL, 3.66 mmol) were added and stirred at room temperature for 30 minutes. The resulting solid was filtered, washed with ethanol to give the target compound (615 mg, 98%, 1.7 mmol) as a pale brown solid.

LC / MS 344.89 [M + H ⁺ ], 688.93 [2M + H ⁺ ].

Step 2: N ¹ - (6- chloro-l- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide Manufacture

N ¹ - (6- chloro-l- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidin-4-yl) benzene-1,4-diamine (500 To a solution of mg, 1.45 mmol) in dichloromethane (10 mL) was added acryloyl chloride (144 mg, 1.59 mmol) and triethylamine (0.40 mL, 2.90 mmol) at 0 ^° C. The reaction mixture was stirred at room temperature for 2 hours. Water was added to terminate the reaction, and extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the title compound as a white solid (380 mg, 66%, 0.95 mmol).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.61-1.90 (m, 4H), 2.05 (brs, 1H), 2.45-2.48 (m, 1H), 3.76-3.82 (m, 1H), 4.08-4.14 ( m, 1H), 5.81 (d, J = 9.9 Hz, 1H), 5.92 (d , J = 9.9 Hz, 1H), 6.24-6.33 (m, 1H), 6.45-6.50 (m, 1H), 7.36 (d , J = 8.4 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.77 (s, 1H), 8.06 (s, 1H); LC / MS 399.00 [M + H ⁺ ], 797.11 [2M + H ⁺ ].

Step 3: Preparation of N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

N ¹ - (6- chloro-l- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (80 mg , 0.20 mmol) in hydrochloric acid (0.08 M, ethoxy ethanol, 2 mL, 10 mmol%) was stirred at 90 ^° C. for 16 h. After cooling the reaction mixture to room temperature, the resulting solid was filtered and washed with ethanol to obtain the target compound (60 mg, 61%, 0.12 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.23 (br, 4H), 3.82 (brs, 4H), 5.76 (d, J = 9.9 Hz, 1H), 6.25 (d, J = 16.8 Hz, 1H ), 6.44-6.53 (m, 1H), 7.14 (brs, 1H), 7.44 (brs, 1H), 7.69 (s, 4H), 8.69 (brs, 1H), 10.11 (brs, 1H), 10.37 (s, 1H), 11.28 (brs, 1 H); LC / MS 457.06 [M + H ⁺ ].

Example 30 Preparation of N ^4, N ⁶ -bis (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine

Step 1: 6-chloro-N- (4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine Manufacture

A solution of 4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (500 mg, 1.83 mmol) in ethanol (20 mL) To 4-morpholinoaniline (195 mg, 1.09 mmol) and Et ₃ N (0.20 mL, 1.46 mmol) were added and stirred at room temperature for 30 minutes. The resulting solid was filtered, washed with ethanol to give the title compound (269 mg, 89%, 0.64 mmol) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.55-1.97 (m, 5H), 2.35 (brs, 1H), 3.12 (brs, 4H), 3.63-3.77 (m, 5H), 3.91-3.95 ( m, 1H), 5.77 (d , J = 9.9 Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 7.58 (brs, 2H) 8.35 (brs, 1H), 10.36 (s, 1H); LC / MS 415.11 [M + H ⁺ ].

Step 2: N ⁴ , N ⁶ -bis (4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4, Preparation of 6-diamine

6-chloro-N- (4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine (50 mg , 0.12 mmol) in 1,4-dioxane (2 mL) in 4-morpholinoaniline (26 mg, 0.15 mmol), Pd ₂ (dba) ₃ (6 mg, 0.006 mmol), Xphos (3 mg, 0.006 mmol), cesium carbonate (118 mg, 0.36 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 120 ^° C. for 20 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under a silica gel column to obtain the title compound (38 mg, 57%, 0.068 mmol) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 1.63-2.10 (m, 5H), 2.48 (brs, 1H), 3.15-3.17 (m, 8H), 3.74-3.89 (brs, 8H), 4.11 (brs, 1 H), 5.77 (d, J = 9.9 Hz, 1 H), 6.93-6.95 (m, 4H), 7.36-7.43 (m, 4H), 7.56-7.59 (m, 2H); LC / MS 557.03 [M + H ⁺ ].

Step 3: Preparation of N ⁴ , N ⁶ -bis (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine

N ⁴ , N ⁶ -bis (4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine To a solution of (33 mg) in methanol (1 mL) was added 4N HCl diethyl ether solution (0.2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with diethyl ether to obtain the title compound (28 mg, 93%, 0.055 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.31 (brs, 8H), 3.88 (brs, 8H), 7.32-7.37 (m, 1H), 7.28-7.49 (m, 6H), 7.71 (brs, 2H), 8.80 (brs, 1 H), 10.34 (s, 1 H), 10.45 (brs, 1 H); LC / MS 473.04 [M + H ⁺ ].

Example 31 Preparation of N ^4- (3-aminophenyl) -N2- (4-morpholinophenyl) -7H-pyrrolo [2, 3-d] pyrimidine-2, 4-diamine

Step 1: Preparation of N ^1- (2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine

4-morpholinoaniline (86 mg, 0.79 mmol) in a solution of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (100 mg, 0.53 mmol) in dimethylsulfoxide (2 mL). ) And diisopropylethylamine (0.19 mL, 1.06 mmol) were added and stirred at 100 ^° C. for 6 hours. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (100 mg, 72%, 0.38 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 5.07 (s, 2H), 6.29 (d, J = 7.8 Hz, 1H), 6.62 (s, 1H), 6.85-6.96 (m, 3H), 7.14 (d, J = 3.3 Hz, 1 H), 9.38 (s, 1 H), 11.80 (s, 1 H); LC / MS 260.09 [M + H ⁺ ].

Step 2: N ^4- (3-aminophenyl) -N ^2- (4-morpholinophenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine Manufacture

N ^1- (2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzene-1,3-diamine (100 mg, 0.39 mmol) in 1,4-dioxane (2 mL 4-morpholinoaniline (111 mg, 0.46 mmol), Pd ₂ (dba) ₃ (18 mg, 0.019 mmol), Xphos (9 mg, 0.019 mmol), cesium carbonate (372 mg, 1.16 mmol). Was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 140 ^° C. for 10 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified using hexane / ethyl acetate under silica gel column to obtain the title compound (31 mg, 21%, 0.077 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 2.98-2.99 (m, 4H), 3.69-3.71 (m, 4H), 4.87 (s, 2H), 6.21 (d, J = 7.5 Hz, 1H) , 6.58 (s, 1H), 6.79-6.84 (m, 3H), 6.88-6.94 (m, 1H), 7.00 (d, J = 7.5 Hz, 1H), 7.25 (s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 8.37 (s, 1 H), 8.75 (s, 1 H), 11.04 (s, 1 H); LC / MS 402.24 [M + H ⁺ ].

Example 32 N- (3-((4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) acrylamide Manufacture

Step 1: N ⁶ - (3- aminophenyl) -N ⁴ - (4- morpholinophenyl) - 1 - (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d ] Preparation of Pyrimidine-4,6-diamine

6-chloro- N- (4-aminophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4- amine (100 mg, 0.24 mmol) in 1,4-dioxane (2 mL) in 1,3-phenylenediamine (39 mg, 0.36 mmol), Pd ₂ (dba) ₃ (11 mg, 0.012 mmol), Xphos (6 mg, 0.012 mmol), cesium carbonate (236 mg, 0.72 mmol) was added. The reaction mixture was degassed with argon for 10 minutes and stirred at 120 ^° C. for 20 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (62 mg, 53%, 0.065 mmol) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.60-1.80 (m, 2H), 1.88-1.93 (m, 1H), 2.00-2.15 (m, 1H), 2.52 (brs, 1H), 3.18-3.20 ( m, 4H), 3.64-3.79 (m, 3H), 3.87-3.89 (m, 4H), 4.11-4.13 (m, 1H), 5.80 (d, J = 9.0 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.89-6.96 (m, 4H), 7.01 (brs, 1H), 7.06-7.11 (m, 1H), 7.19 (brs, 1H), 7.35 (d, J = 9.0 Hz, 2H); LC / MS 487.00 [M + H ⁺ ].

Step 2: N- (3-((4-((4-morpholinophenylamino) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] Preparation of pyrimidin-6-yl) amino) phenyl) acrylamide

N ⁶ - (3- aminophenyl) -N ⁴ - (4- morpholinophenyl) - 1 - (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d] pyrimidine In a solution of -4,6-diamine (50 mg, 0.10 mmol) in dichloromethane (2 mL), acrylic acid (0.008 mL, 0.12 mmol), 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide ( 30 mg, 0.16 mmol), hydroxybenzotriazole (21 mg, 0.16 mmol), diisopropylethylamine (0.04 mL, 0.21 mmol) were added and stirred at room temperature for 4 hours. Water was added to the reaction mixture to terminate the reaction and extracted twice with dichloromethane. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (35 mg, 64%, 0.953 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.52 (brs, 2H), 1.77-1.81 (m, 2H), 1.96 (brs, 1H), 2.34-2.39 (m, 1H), 3.04 (brs, 4H), 3.72 (brs, 5H), 3.87-3.91 (m, 1H), 5.72-5.74 (m, 1H), 5.87-5.98 (m, 1H), 6.14-6.26 (m, 1H), 6.41-6.51 ( m, 1H), 6.90 (d, J = 8.7 Hz, 2H), 7.00 (d , J = 7.2 Hz, 1H), 7.12-7.18 (m, 1H), 7.28 (d , J = 8.4 Hz, 2H), 7.99 (br, 1 H), 8.74 (br, 1 H), 9.25 (s, 1 H), 9.56 (s, 1 H), 10.04 (s, 1 H); LC / MS 540.11 [M + H ⁺ ].

Step 3: N ⁶ - (3- aminophenyl) -N ⁴ - (4- morpholinophenyl) - 1 - (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3,4-d ] Preparation of Pyrimidine-4,6-diamine

N- (3-((4-((4-morpholinophenylamino) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine To a solution of -6-yl) amino) phenyl) acrylamide (30 mg) in methanol (1 mL) was added hydrochloric acid solution (4N, diethyl ether, 0.2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, washed with diethyl ether to obtain the title compound (25 mg, 93%, 0.051 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.09 (brs, 4H), 3.74 (brs, 4H), 5.74 (d, J = 11.4 Hz, 1H), 6.23 (d, J = 16.8 Hz, 1H ), 6.46-6.51 (m, 1H), 6.95 (brs, 2H), 7.23-7.52 (m, 3H), 7.62 (br, 2H), 7.81 (s, 1H), 8.60 (brs, 1H), 10.32 ( s, 1 H), 11.10 (br s, 1 H); LC / MS 457.10 [M + H ⁺ ], 913.89 [2M + H ⁺ ].

Example 33 Preparation of N- (3-((2-((4-morpholinophenyl) amino) -9H-purin-6-yl) amino) phenyl) acrylamide

Step 1: Preparation of 2,6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

3,4-dihydro-2H-pyran (360 mg, 4.3 mol) and p-toluenesulfonic acid in a solution of 2,6-dichloro-9H-purine (300 mg, 1.59 mol) in ethyl acetate (5 mL) (8 mg, 0.05 mmol) was added and stirred at 50 ^° C. for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and then purified by silica gel column to obtain the target compound (301 mg, 70%, 1.1 mmol) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.64-2.19 (m, 6H), 3.75-3.83 (m, 1H), 4.17-4.21 (m, 1H), 5.77 (dd, J = 2.4 Hz, 10.8 Hz , 1H), 8.34 (s, 1 H); LC / MS 273.08 [M + H ⁺ ].

Step 2: Preparation of N- (3-((2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) phenyl) acrylamide

N- (3-aminophenyl) acrylic in a solution of 2,6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (100 mg, 0.37 mmol) in ethanol (2 mL) Amide (65 mg, 0.40 mmol) and triethylamine (0.13 mL, 0.92 mmol) were added and stirred at 80 ^° C. for 12 h. The reaction mixture was cooled to room temperature, distilled under reduced pressure, water was added, and extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (78 mg, 56%, 0.19 mmol) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.26-1.75 (m, 3H), 1.93-2.10 (m, 3H), 3.69-3.76 (m, 1H), 4.11 (d, J = 12.6 Hz, 1H) , 5.66-5.72 (m, 2H), 6.26-6.43 (m, 2H), 7.19-7.28 (m, 1H), 7.37-7.46 (m, 2H), 7.94 (s, 1H), 8.02 (s, 1H) , 8.27 (s, 1 H), 8.33 (s, 1 H); LC / MS 399.00 [M + H ⁺ ], 797.31 [2M + H ⁺ ].

Step 3: Preparation of N- (3-((2-((4-morpholinophenyl) amino) -9H-purin-6-yl) amino) phenyl) acrylamide

N- (3-((2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) phenyl) acrylamide (50 mg, 0.13 mmol) in HCl solution 4-morpholinoaniline (27 mg, 0.15 mmol) was added to the solution dissolved in (0.08 M, ethoxyethanol, 1.5 mL), followed by stirring at 100 ^° C. for 12 hours. After cooling the reaction mixture to room temperature, the resulting solid was filtered and washed with ethanol to obtain the target compound (35 mg, 57%, 0.070 mmol) as a gray solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.11 (brs, 4H), 3.78 (m, 4H), 5.76 (d, J = 10.8 Hz, 1H), 6.27 (d, J = 17.1 Hz, 1H ) 6.45-6.59 (m, 1H), 6.96-7.05 (m, 2H), 7.18-7.31 (m, 2H), 7.45-7.67 (m, 3H), 8.16 (s, 1H), 8.55 (s, 1H) , 9.40 (s, 1 H), 10.22 (s, 1 H), 10.38 (s, 1 H); LC / MS 457.19 [M + H ⁺ ].

Example 34 Preparation of N- (3-((2-((4-morpholinophenyl) amino) pyrido [2, 3-d] pyrimidin-4-yl) amino) phenyl) acrylamide

Step 1: Preparation of N- (3-((2-chloropyrido [2,3-d] pyrimidin-4-yl) aminophenyl) phenyl) acrylamide

N- (3-aminophenyl) acrylamide (81 mg, 0.49 mmol) in a solution of 2,4-dichloropyrido [2,3-d] pyrimidine (100 mg, 0.49 mmol) in ethanol (2 mL). And diisopropylethylamine (0.22 mL, 1.25 mmol) were added and stirred at room temperature for 4 hours. The resulting solid was filtered and washed with ethanol to give the target compound (126 mg, 78%, 0.38 mmol) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 5.75 (d , J = 10.2 Hz, 1H), 6.25 (dd, J = 1.8 Hz, 17.1 Hz, 1H), 6.41-6.50 (m, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.63-7.67 (m, 1H), 8.09 (s, 1H), 9.00-9.04 (m, 2H), 10.25 (s, 1H), 10.45 (s, 1H) ; LC / MS 326.02 [M + H ⁺ ], 651.10 [2M + H ⁺ ].

Step 2: Preparation of N- (3-((2-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-4-yl) amino) phenyl) acrylamide

N- (3-((2-chloropyrido [2,3-d] pyrimidin-4-yl) aminophenyl) phenyl) acrylamide (100 mg, 0.35 mmol) with hydrochloric acid (0.08 M, ethoxyethanol solution , 3 mL), and then stirred at 100 ^° C. for 45 minutes. After the reaction mixture was cooled to room temperature, the resulting solid was filtered, the filtered solid was dissolved in an aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent, and then purified by silica gel column to give the title compound as a yellow solid. (116 mg, 81%, 0.173 mmol) was obtained.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 2.98 (brs, 4H), 3.70 (brs, 4H), 5.74 (d, J = 12.0 Hz, 1H), 6.25 (d, J = 16.8 Hz, 1H ), 6.41-6.50 (m, 1H), 6.79-6.81 (m, 2H), 7.17-7.21 (m, 1H), 7.28-7.34 (m, 1H) 7.38 (d, J = 6.5 Hz, 1H), 7.67 (brs, 1 H), 8.05 (s, 1 H), 8.72-8.74 (m, 2 H), 9.13 (brs, 1 H), 9.82 (brs, 1 H), 10.18 (s, 1 H); LC / MS 467.18 [M + H ⁺ ], 935.62 [2M + H ⁺ ].

Example 35 Preparation of N- (3-((4-((4-morpholinophenyl) amino) pyrido [2, 3-d] pyrimidin-2-yl) amino) phenyl) acrylamide

Step 1: Preparation of 2-chloro-N- (4-morpholinophenyl) pyrido [2,3-d] pyrimidin-4-amine

4-morpholinoaniline (196 mg, 1.09 mmol) and diisopropyl in a solution of 2,4-dichloropyrido [2,3-d] pyrimidine (200 mg, 0.99 mmol) in ethanol (2 mL) Ethylamine (0.44 mL, 2.49 mmol) was added and stirred at room temperature for 6 hours. The resulting solid was filtered and washed with ethanol to give the title compound (305 mg, 78%, 0.89 mmol) as a pale green solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.11-3.12 (m, 4H), 3.73-3.74 (m, 4H), 7.00 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.61-7.65 (m, 1H), 8.94 (d, J = 8.7 Hz, 1H), 9.01 (d, J = 4.2 Hz, 1H), 10.35 (s, 1H); LC / MS 341.98 [M + H ⁺ ], 683.23 [2M + H ⁺ ].

Step 2: Preparation of N- (3-((4-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide

2-chloro-N- (4-morpholinophenyl) pyrido [2,3-d] pyrimidin-4-amine (50 mg, 0.15 mmol)) was dissolved in dimethylacetamide (3 mL). -(3-aminophenyl) acrylamide (28 mg, 0.18 mmol) was added and stirred at 80 ^° C. for 6 hours. The reaction mixture was cooled to room temperature and the resulting solid was filtered to yield the target compound (38 mg, 56%, 0.081 mmol) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.09 (brs, 4H), 3.74 (brs, 4H), 5.76 (d, J = 11.1 Hz, 1H), 6.25 (d, J = 15.9 Hz, 1H ), 6.45-6.54 (m, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.23-7.28 (m, 1H), 7.35 (brs, 1H), 7.46 (d, J = 7.8 Hz, 1H) , 7.47-7.58 (m, 3H), 7.89 (brs, 1H), 8.80 (d, J = 4.8 Hz, 1H), 9.14 (d, J = 7.8 Hz, 1H), 10.36 (s, 1H), 10.46 ( s, 1 H), 10.94 (brs, 1 H); LC / MS 468.12 [M + H ⁺ ], 935.62 [2M + H ⁺ ].

Example 36 Preparation of N ^2, N ⁴ -bis (4-morpholinophenyl) pyrido [2, 3-d] pyrimidine-2,4-diamine

Step 1: Preparation of 2-chloro- N- (4-morpholinophenyl) pyrido [2,3-d] pyrimidin-4-amine

4-morpholinoaniline (196 mg, 1.1 mmol) and diisopropyl in a solution of 2,4-dichloropyrido [2,3-d] pyrimidine (200 mg, 0.99 mmol) in ethanol (2 mL) Ethylamine (0.44 mL, 2.49 mmol) was added and stirred at room temperature for 6 hours. The resulting solid was filtered and washed with ethanol to give the title compound (305 mg, 78%, 0.89 mmol) as a pale green solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.11-3.12 (m, 4H), 3.73-3.74 (m, 4H), 7.00 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.61-7.65 (m, 1H), 8.94 (d, J = 8.7 Hz, 1H), 9.01 (d, J = 4.2 Hz, 1H), 10.35 (s, 1H); LC / MS 341.98 [M + H ⁺ ], 683.23 [2M + H ⁺ ].

Step 2: Preparation of N ² , N ⁴ -bis (4-morpholinophenyl) pyrido [2,3-d] pyrimidine-2,4-diamine

2-chloro- N- (4-morpholinophenyl) pyrido [2,3-d] pyrimidin-4-amine (50 mg, 0.15 mmol)) was dissolved in dimethylacetamide (3 mL). -Morpholinoaniline (32 mg, 0.18 mmol) was added and then stirred at 80 ^° C. for 4 hours. After cooling the reaction mixture to room temperature, the resulting solid was filtered to give the target compound (41 mg, 59%, 0.085 mmol) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.06-3.15 (m, 8H), 3.75-3.76 (m, 8H), 6.89 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 7.39-7.61 (m, 5H ), 8.77 (d, J = 4.2 Hz, 1H), 8.91 (d, J = 7.8 Hz, 1H), 9.77 (br, 1H), 10.41 (br, 1H); LC / MS 484.24 [M + H ⁺ ], 968.02 [2M + H ⁺ ].

Example 37 N- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -3-methyl-1H-pyrazolo [3,4-d] pyrid Preparation of midin-4-yl) amino) phenyl) acrylamide

Step 1: 1- (4- (4-((3-methyl-4-((3-nitrophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3 Preparation of, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) ethanone

6-chloro-3-methyl-N- (3-nitrophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d in t- butanol (2 mL) ] Dissolve pyrimidin-4-amine (50 mg, 0.12 mmol), 1- (4- (4-aminophenyl) piperazin-1-yl) ethanone (36 mg, 0.16 mmol) and Pd ₂ (dba) ₃ (1.2 mg, 0.0013 mmol), XPhos (1.7 mg, 0.0038 mmol), potassium carbonate (43 mg, 0.31 mmol) is added, charged with nitrogen and stirred at 90 ^° C. for 14 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (32 mg, 43.5%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 7.95-7.93 (d, 2H), 7.49-7.44 (d, 2H), 6.99-6.95 (d, 2H), 6.91-6.88 (d , 2H), 5.77-5.74 (d, 1H), 4.15-4.13 (d, 1H), 3.82-3.75 (t, 3H), 3.65-3.62 (t, 3H), 3.16-3.09 (m, 4H), 2.66 (s, 3H), 2.15 (s, 3H), 1.92-1.87 (d, 1H), 1.80-1.69 (m, 5H).

Step 2: 1- (4- (4-((4-((3-aminophenyl) amino) -3-methyl-1- (tetrahydro-2H-pylan-2-yl) -1H-pyrazolo [3 Preparation of, 4-d] pyrimidin-6-yl) amino) phenyl) filperazin-1-yl) ethanone

1- (4- (4-((3-methyl-4-((3-nitrophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyra in methanol (2 mL)) After dissolving zolo [3,4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) ethanone (30 mg, 0.052 mmol), Zn (17 mg, 0.26 mmol), ammonium foam Mate (17 mg, 0.26 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, ethyl acetate / water was added, the product was extracted with the organic layer, the organic layer was dried and concentrated to obtain the product, and the next reaction was carried out without purification.

Step 3: N- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -3-methyl-1- (tetrahydro-2H-pyran-2-yl) Preparation of -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

1- (4- (4-((4-((3-aminophenyl) amino) -3-methyl-1- (tetrahydro-2H-phylan-2-yl) -1H- in dichloromethane (4 mL) Pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) filperazin-1-yl) ethanone (22 mg, 0.041 mmol) is added thereto and acrylic acid (3.1 uL, 0.045 mmol) , 1-ethyl-3- (3-dimethylaminopyridine) carbodiimide (32 mg, 0.21 mmol), hydroxybenzotriazole (28 mg, 0.21 mmol), diisopropylethylamine (38 mL, 0.21 mmol) After all the addition, it is stirred for 14 hours at room temperature. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (2.7 mg, 3.3%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.25 (b, 1H), 7.59-7.56 (d, 2H), 7.43 (b, 1H), 7.33-7.30 (m, 2H), 7.10 (s, 1H), 6.94-6.93 (d, 2H), 6.87 (s, 1H), 6.51-6.47 (d, 1H), 6.30-6.25 (q, 1H), 5.81-5.77 (t, 2H), 4.17-4.16 (d, 1H ), 3.81-3.77 (t, 4H), 3.66-3.61 (m, 4H), 3.16-3.11 (m, 4H), 2.67 (s, 3H), 2.17 (s, 1H), 1.80-1.69 (m, 5H ).

Step 4: N- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -3-methyl-1H-pyrazolo [3,4-d] pyrimidine- Preparation of 4-ylamino) phenyl) acrylamide

N- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H- Pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (4 mg 0.0067 mmol) was added to methanol (1 mL) and added hydrochloric acid (4M, 1,4-dioxane, 1 mL) is added and stirred at room temperature for 15 minutes. When the reaction was terminated, the solvent was removed and recrystallized with ether to obtain the target compound. (3.2 mg, 93%)

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.85 (s, 1H), 7.67-7.55 (d, 2H), 7.49-.7.33 (m, 2H), 7.29-7.19 (m, 3H), 6.47- 6.38 (m, 2H), 5.83-5.77 (d, 1H), 4.17-4.16 (d, 1H), 3.81-3.77 (t, 4H), 3.66-3.61 (m, 4H), 2.67 (s, 3H), 2.17 (s, 1 H), 1.80-1.69 (m, 5 H).

Example 38 N- (3-((6-((4- (1-methyl-5, 6-dihydro-1, 2, 4-triazin-4 (1H) -yl) phenyl) amino) Preparation of -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

N- (3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (50 mg, 0.13 mmol) and HCl (0.08 M, ethoxyethanol solution, 1.3 mL) were mixed and then 4- (1-methyl-5,6-dihydro-1,2,4-triazine-4 ( 1H) -yl) aniline (27 mg, 0.15 mmol) was added and stirred at 100 ^° C. for 6 hours. After cooling the reaction mixture to room temperature, an aqueous solution of sodium bicarbonate was added to terminate the reaction, and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (15 mg, 26%, 0.032 mmol) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ 2.71 (s, 3H), 2.95-2.98 (m, 2H), 3.76-3.79 (m, 2H), 5.78 (dd, J = 3.0 Hz, 8.9 Hz, 1H), 6.39-6.43 (m, 2H), 6.99 (d, J = 8.7 Hz, 2H), 7.24 (s, 1H), 7.27-7.33 (m, 1H), 7.40 (d , J = 7.8 Hz, 1H ), 7.48 (d , J = 7.8 Hz, 1H), 7.70 (d, J = 9.0 Hz, 2H), 8.01 (s, 1H), 8.30 (s, 1H); LC / MS 413.36 [M + H ⁺ ].

Example 39 1- (6-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1- (1) Preparation of prope-2-en-1-one

Step 1: 1- (6-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indole Preparation of Lin-1-yl) prope-2-en-1-one

4,6-Dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (100 mg, 0.37 mmol) in ethanol (2 mL) To 1- (6-aminoindolin-1-yl) prope-2-en-1-one (76 mg, 0.40 mmol) and triethylamine (0.13 mL, 0.92 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Stirred. The reaction mixture was cooled to 0 ^° C., the resulting solid was filtered and washed with ethanol to give the title compound (118 mg, 76%, 0.24 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.56-2.03 (m, 5H), 2.32-2.43 (m, 1H), 3.15-3.19 (m, 2H), 3.65-3.73 (m, 1H), 3.94 (d, J = 11.7 Hz, 1H), 4.24-4.27 (m, 2H), 5.77-5.86 (m, 2H), 6.32 (d, J = 16.5 Hz, 1H), 6.72-6.81 (m, 1H) , 7.30 (d , J = 8.1 Hz, 1H), 7.67 (brs, 1H), 8.38 (brs, 1H), 10.56 (s, 1H); LC / MS 425.16 [M + H ⁺ ], 849.63 [2M + H ⁺ ].

Step 2: 1- (6-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) Preparation of Prope-2-en-1-one

1- (6-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1 -Yl) prope-2-en-1-one (50 mg, 0.12 mmol) and hydrochloric acid (0.08M, ethoxyethanol solution, 1.2 mL) followed by 4-morpholinoaniline (25 mg, 0.14 mmol ) ^Was added and stirred at 90 ^° C. for 6 hours. After the reaction mixture was cooled to room temperature, an aqueous sodium bicarbonate solution was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (15 mg, 27%, 0.031 mmol) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 2.96-3.08 (m, 4H), 3.16-3.18 (m, 2H), 3.73-3.76 (m, 4H), 4.09-4.11 (m, 2H), 4.82 (d, J = 9.3 Hz, 1H), 6.31 (d , J = 18.0 Hz, 1H), 6.74-6.86 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 8.7 Hz, 2H), 8.06 (s, 1H), 8.33 (s, 1H), 8.87 (s, 1H), 9.71 (s, 1H), 12.85 (s, 1H); LC / MS 483.29 [M + H ⁺ ].

Example 40 1- (6-((2-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-4-yl) amino) indolin-1-yl) Preparation of Prope-2-en-1-one

Step 1: Preparation of 1- (6-((2-chloropyrido [2,3-d] pyrimidin-4-yl) amino) indolin-1-yl) prope-2-en-1-one

1- (6-aminoindolin-1-yl) prope in a solution of 2,4-dichloropyrido [2,3-d] pyrimidine (100 mg, 0.50 mmol) in n-butanol (2 mL) 2-en-1-one (103 mg, 0.55 mmol) and diisopropylethylamine (0.22 mL, 1.25 mmol) were added and stirred at room temperature for 4 hours. The reaction mixture was cooled to 0 ^° C., and the resulting solid was filtered and washed with ethanol to obtain the target compound (166 mg, 95%, 0.47 mmol) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.19 (t, J = 8.1 Hz, 2H), 4.28 (t, J = 8.4 Hz, 2H), 5.85 (d, J = 10.5 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 6.73-6.82 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 6.5 Hz, 1H), 7.65-7.69 (m , 1H), 8.46 (s, 1H), 9.03-9.05 (m, 2H), 10.52 (s, 1H); LC / MS 351.16 [M + H ⁺ ], 703.41 [2M + H ⁺ ].

Step 2: 1- (6-((2-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-4-yl) amino) indolin-1-yl) prope Preparation of 2-en-1-one

1- (6-((2-chloropyrido [2,3-d] pyrimidin-4-yl) amino) indolin-1-yl) prope-2-en-1-one (50 mg, 0.14 mmol) and hydrochloric acid (0.08M, ethoxyethanol solution, 1.4 mL) were mixed, then 4-morpholinoaniline (30 mg, 0.17 mmol) was added and stirred at 90 ^° C. for 6 hours. After cooling the reaction mixture to room temperature, an aqueous solution of sodium bicarbonate was added to terminate the reaction, and extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the target compound (25 mg, 36%, 0.051 mmol) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.02 (br, 4H), 3.19 (t, J = 8.4 Hz, 2H), 3.73-3.74 (m, 4H), 4.25 (t, J = 8.4 Hz , 2H), 5.83 (d , J = 8.4 Hz, 2H), 6.31 (d , J = 16.8 Hz, 1H), 6.75-6.84 (m, 3H), 7.19-7.28 (m, 2H), 7.85 (brs, 3H), 8.32-8.40 (m, 1H), 8.75-8.79 (m, 2H), 9.16 (s, 1H), 9.82 (s, 1H); LC / MS 494.29 [M + H ⁺ ].

Example 41 N- (3-((6-((3-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide Manufacture

N- (3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (100 mg, 0.25 mmol) and hydrochloric acid (0.08 M, ethoxyethanol solution, 2.5 mL) were mixed, and 3-morpholinoaniline (54 mg, 0.30 mmol) was added thereto and stirred at 90 ^° C. for 2 hours. . After the reaction mixture was cooled to room temperature, an aqueous solution of sodium bicarbonate was added to terminate the reaction, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (26 mg, 0.057 mmol, 23%).

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.06 (brs, 4H), 3.74 (brs, 4H), 5.78 (d, J = 9.6 Hz, 1H), 6.29 (d, J = 18.0 Hz, 1H ), 6.44-6.55 (m, 2H), 7.07-7.12 (m, 1H), 7.32-7.38 (m, 3H), 7.46 (s, 1H), 7.92 (s, 1H), 8.12 (s, 2H), 9.79 (s, 1 H), 10.13 (s, 1 H), 12.98 (s, 1 H); LC / MS 457.26 [M + H ⁺ ].

Example 42 Preparation of N- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

Step 1: N- (3-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) phenyl) acrylamide

N- (3-((6-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was dissolved 4-phenoxyphenylboronic acid (32 mg, 0.15 mmol) and sodium carbonate. After adding (40 mg, 0.37 mmol) aqueous solution (1 mL), the reaction mixture was degassed with argon for 10 minutes and stirred at 110 ^° C. for 10 minutes using a microwave reactor. After the reaction mixture was cooled to room temperature, water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (49 mg, 0.092 mmol, 74%) as white.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.79-2.11 (m, 5H), 2.58-2.62 (m, 1H), 3.79-3.86 (m, 1H), 4.13-4.16 (m, 1H), 5.69 ( d , J = 10.2 Hz, 1H), 6.08 (d, J = 10.5 Hz, 1H), 6.23 (dd , J = 9.9 Hz, 17.1 Hz, 1H), 6.38 (d, J = 17.1 Hz, 1H), 7.01 -7.11 (m, 4H), 7.14-7.16 (m, 1H), 7.21-7.26 (m, 2H), 7.34-7.39 (m, 3H), 7.55 (s, 1H), 7.69 (brs, 1H), 7.88 (s, 2H), 8.45 (d, J = 8.1 Hz, 2H); LC / MS 533.41 [M + H ⁺ ].

Step 2: Preparation of N- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide

N- (3-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) To a solution of amino) phenyl) acrylamide (30 mg) in methanol (1 mL) and diethyl ether (2 mL) was mixed a solution of hydrochloric acid (5 M, ethyl ether, 2 mL) and stirred at room temperature for 30 minutes. I was. After distilling the reaction mixture under reduced pressure, an aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the target compound (15 mg, 0.033 mmol, 60%) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 5.76 (d, J = 10.2 Hz, 1H), 6.26 (d , J = 16.8 Hz, 1H), 6.49 (dd, J = 9.9 Hz, 17.1 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.37-7.49 (m, 3H), 7.72 (d, J = 8.1 Hz, 1H), 8.34 ( br, 1H), 8.51 (d, J = 8.1 Hz, 2H), 8.58 (s, 1H); LC / MS 449.23 [M + H ⁺ ].

Example 43 1- (6-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) prop Preparation of Phen-2-en-1-one

Step 1: 1- (6-((6-chloro-1- (1-tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino Preparation of Indolin-1-yl) propen-2-en-1-one

A solution of 4,6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (500 mg, 1.83 mmol) in ethanol (5 mL) To 1- (6-aminoindolin-1-yl) prope-2-en-1-one (380 mg, 2.01 mmol) and triethylamine (0.64 mL, 4.6 mmol) were added and stirred at room temperature for 4 hours. I was. After cooling the reaction mixture to 0 ^o C, the resulting solid was filtered and washed with ethanol to obtain the target compound (770 mg, 1.8 mmol, 76%) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.57-2.03 (m, 5H), 2.33-2.44 (m, 1H), 3.52-3.21 (m, 2H), 3.65-3.74 (m, 1H), 3.94-3.98 (m, 1H), 4.25-4.30 (m, 2H), 5.78-5.87 (m, 2H), 6.33 (d, J = 16.5 Hz, 1H), 6.77 (dd, J = 11.1 Hz, 16.5 Hz , 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.65 (br, 1H), 8.39 (br, 2H), 10.57 (s, 1H); LC / MS 425.23 [M + H ⁺ ], 849.83 [2M + H ⁺ ].

Step 2: 1- (6-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4 Preparation of -yl) amino) indolin-1-yl) propen-2-en-1-one

1- (6-((6-chloro-1- (1-tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin -1-yl) propen-2-en-1-one (50 mg, 0.12 mmol) in a solution of 1,4-dioxane (2 mL) (4-phenoxyphenyl boronic acid (30 mg, 0.14) mmol), sodium carbonate (37 mg, 0.35 mmol) aqueous solution (1 mL), PdCl ₂ (PPh ₃ ) ₂ After addition of (6 mg, 0.008 mmol), the reaction mixture was degassed with argon for 10 minutes and stirred at 110 ^° C. for 10 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction, and extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (30 mg, 0.054 mmol, 46%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.71-2.17 (m, 5H), 2.55-2.58 (m, 1H), 3.16-3.19 (m, 2H), 3.77-3.84 (m, 1H), 4.11- 4.14 (m, 3H), 5.62 (brs, 1H), 6.07 (d, J = 16.5 Hz, 1H), 6.77 (dd, J = 10.5 Hz, 1H), 6.41 (brs, 2H), 8.39 (brs, 2H ), 7.08-7.17 (m, 6H), 7.35-7.40 (m, 2H), 7.61 (brs, 2H), 8.52-8.55 (m, 3H); LC / MS 475.33 [M + H ⁺ ], 950.00 [2M + H ⁺ ].

Step 3: 1- (6-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) prope- Preparation of 2-en-1-one

1- (6-((6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) Amino) indolin-1-yl) prope-2-en-1-one (25 mg, 0.051 mmol) was dissolved in methanol (1 mL) and diethyl ether (2 mL) in hydrochloric acid (5 N, di Ethyl ether, 0.2 mL) solution was mixed and stirred at room temperature for 30 minutes. After distilling the reaction mixture under reduced pressure, an aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (20 mg, 0.042 mmol, 95%) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 3.15-3.19 (m, 2H), 4.26-4.31 (m, 2H), 5.81 (d, J = 10.2 Hz, 1H), 6.27 (d, J = 16.8 Hz, 1H), 6.79 (dd , J = 11.1 Hz, 17.1 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.21-7.26 (m , 1H), 7.30 (d, J = 18.1 Hz, 1H), 7.45-7.49 (m, 2H), 7.60 (d , J = 8.4 Hz, 1H), 8.32 (brs, 1H), 8.57 (d, J = 8.7 Hz, 2H), 9.04 (brs, 1H), 10.06 (s, 1H), 13.60 (s, 1H); LC / MS 475.33 [M + H ⁺ ], 950.00 [2M + H ⁺ ].

Example 44 1- (6-((3-methyl-6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1 Preparation of Propyl-2-en-1-one

Step 1: Preparation of 4, 6-dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine Step 1: 4,6- Preparation of dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine

4,6-Dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (500 mg, 2.46 mmol) was diluted with ethyl acetate (5 3,4-dihydro-2 H -pyran (0.61 mL, 0.56 mmol) and p-toluenesulfonic acid (13 mg, 0.074 mmol) were added to the solution, and the reaction mixture was added at 50 ^° C. Stir for hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and then purified by silica gel column to obtain the target compound (700 mg, 2.5 mmol, 99%) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.58-2.04 (m, 5H), 2.36-2.40 (m, 1H), 2.65 (s, 3H), 3.69-3.77 (m, 1H), 3.94- 3.98 (m, 1 H), 5.88 (d, J = 9.6 Hz, 1 H); LC / MS 287.22 [M + H ⁺ ].

Step 2: 1- (6-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl Preparation of Amino) Indolin-1-yl) prope-2-en-1-one

4,6-Dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (500 mg, 1.74 mmol) in ethanol (5 mL 1- (6-aminoindolin-1-yl) prope-2-en-1-one (361 mg, 1.92 mmol) and triethylamine (0.61 mL, 4.4 mmol) were added to the solution dissolved in the mixture. Stirred for 4 hours. After cooling the reaction mixture to 0 ^o C, the resulting solid was filtered and washed with ethanol to obtain the target compound (710 mg, 1.62 mmol, 76%) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 1.56-2.00 (m, 5H), 2.35-2.39 (m, 1H), 2.63 (m, 3H), 3.16-3.22 (m, 2H), 3.68- 3.69 (m, 1H), 3.93-3.97 (m, 1H), 4.26-4.29 (m, 2H), 5.72 (d, J = 9.9 Hz, 1H), 5.85 (d, J = 11.1 Hz, 1H), 6.32 (d , J = 16.8 Hz, 1H), 6.74-6.77 (m, 1H), 7.28 (s, 1H), 8.33 (s, 1H), 9.21 (s, 1H); LC / MS 439.25 [M + H ⁺ ], 877.84 [2M + H ⁺ ].

Step 3: 1- (6-((3-methyl-6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] Preparation of pyrimidin-4-yl) amino) indolin-1-yl) prope-2-en-1-one

1- (6-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) 4-phenoxyphenyl boronic acid (29 mg, in a solution of indolin-1-yl) propen-2-en-1-one (50 mg, 0.11 mmol) in 1,4-dioxane (2 mL) 0.14 mmol), Na ₂ CO ₃ (36 mg, 0.34 mmol) in aqueous solution (1 mL), PdCl ₂ (PPh ₃ ) ₂ After addition of (6 mg, 0.008 mmol), the reaction mixture was degassed with argon for 10 minutes and stirred at 110 ^° C. for 10 minutes using a microwave reactor. After cooling the reaction mixture to room temperature, water was added to terminate the reaction and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure to remove the solvent, and then purified by silica gel column to obtain the target compound (53 mg, 0.093 mmol, 82%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.60-2.14 (m, 5H), 2.55-2.66 (m, 1H), 2.73 (s, 3H), 3.18-3.23 (m, 2H), 3.78-3.85 ( m, 1H), 4.11-4.24 (m, 3H), 5.78 (brs, 1H), 6.13 (d, J = 10.5 Hz, 1H), 6.35-6.93 (m, 2H), 7.01 (s, 1H), 7.06 -7.16 (m, 5H), 7.21 (d, J = 8.1 Hz, 1H), 7.34-7.39 (m, 2H), 7.78 (brs, 1H), 8.54-8.56 (m, 3H); LC / MS 473.49 [M + H ⁺ ].

Step 4: 1- (6-((3-methyl-6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl Preparation of prope-2-en-1-one

1- (6-((3-methyl-6- (4-phenoxyphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- 4-yl) amino) indolin-1-yl) propen-2-en-1-one (40 mg) in a solution of methanol (1 mL) and diethyl ether (2 mL) in hydrochloric acid (5 N, Diethyl ether, 0.2 mL) was mixed and stirred at room temperature for 30 minutes. The reaction mixture was distilled under reduced pressure, an aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over magnesium sulfate, filtered, distilled under reduced pressure, solvent removed, and purified by silica gel column to obtain the target compound (15 mg, 0.031 mmol, 44%) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 2.73 (s, 3H), 3.18 (t, J = 7.8 Hz, 2H), 4.29 (t, J = 7.8 Hz, 2H), 5.79 (d, J = 11.1 Hz, 1H), 6.25 (d, J = 16.5 Hz, 1H), 6.79 (dd, J = 9.9 Hz, 16.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.20-7.29 (m, 2H), 7.39-7.48 (m, 3H), 7.39-7.48 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 8.64 (s , 1H), 8.91 (br, 1H), 13.21 (s, 1H); LC / MS 489.36 [M + H ⁺ ], 978.08 [2M + H ⁺ ].

Example 45 N- (3-((3-methyl-4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) Preparation of Phenyl) acrylamide

Step 1: 6-chloro-3-methyl-N- (4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine Preparation of 4-amine

4,6-dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (200 mg, 0.69 mmol) was added to dimethylformamide ( 1 mL), 4-morpholinoaniline (149 mg, 0.84 mmol), potassium carbonate (241 mg, 1.7 mmol) is added and stirred at room temperature for 14 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.27 (d, 2H), 6.99-6.96 (d, 2H), 5.78-5.74 (m, 1H), 4.13-4.11 (m, 2H), 3.62-3.58 (m, 2H), 3.17-3.14 (t, 4H), 2.62 (s, 3H).

Step 2: 3-methyl -N ⁴ - (4- morpholinophenyl) -N ⁶ - (3-nitrophenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3 , 4-d] pyrimidine-4,6-diamine

6-chloro-3-methyl-N- (4-morpholinophenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-4- Amine (100 mg, 0.23 mmol) was added to t-butanol (2 mL), 3-nitroaniline (36 mg, 025 mmol), Pd ₂ (dba) ₃ (1 mg, 0.023 mmol), X- phos (1 mg, 0.069 mmol), potassium carbonate (67 mg, 0.48 mmol) was added and stirred at 90 ^° C. for 14 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.79 (d, J = 6.1 Hz, 1H), 7.47-7.42 (m, 4H), 7.37-7.32 (t, 1H), 6.90-6.87 (d, J = 8.94 Hz, 2H), 5.87-5.83 (d, J = 10.8 Hz, 1H),), 4.13-4.11 (m, 2H), 3.62-3.58 (m, 2H), 3.89-3.86 (t, 4H), 3.17-3.14 (t, 4H), 2.62 (s, 3H), 2.09-2.02 (m, 4H),

Step 3: N ⁶ - (3- aminophenyl) -3-methyl -N ⁴ - (4- morpholinophenyl) - 1 - (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3 , 4-d] pyrimidine-4,6-diamine

3-methyl -N ⁴ - (4- morpholinophenyl) -N ⁶ - (3-nitrophenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3, 4- d] pyrimidine-4,6-diamine (58 mg, 0.11 mmol) is added to methanol (1 mL), zinc (36 mg, 0.54 mmol), ammonium formate (35 mg, 0.55 mmol) is added and at room temperature Stir for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, and then the organic layer was dried over anhydrous forget-me-not, filtered and concentrated, and then subjected to the next reaction.

Step 4: N- (3-((3-methyl-4-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3, Preparation of 4-d] pyrimidin-6-yl) amino) phenyl) acrylamide

N ⁶ - (3- aminophenyl) -3-methyl -N ⁴ - (4- morpholinophenyl) - 1 - (tetrahydro -2H- pyran-2-yl) -1H- pyrazolo [3, 4- d] pyrimidine-4,6-diamine (40 mg, 0.080 mmol) is added to dichloromethane (2 mL) and acrylic acid (7 mg, 0.096 mmol), 1-ethyl-3- (3-dimethylaminopyridine) Bodyimide (23 mg, 0.12 mmol), hydroxybenzotriazole (17 mg, 0.12 mmol) and diisopropylethylamine (30 νL, 0.16 mmol) were added, followed by stirring at room temperature for 12 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (25 mg, 57%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52-7.50 (d, J = 8.85 Hz, 2H), 7.24-7.12 (m, 4H), 6.95-6.92 (d, J = 8.85 Hz, 1H), 6.47- 6.41 (m, 1H), 6.29-6.26 (m, 1H), 5.93-5.89 (m, 1H), 5.78-5.74 (m, 1H), 4.13-4.11 (m, 2H), 3.62-3.58 (m, 2H ), 3.89-3.86 (t, 4H), 3.17-3.14 (t, 4H), 2.62 (s, 3H), 2.09-2.02 (m, 4H).

Step 5: N- (3-((3-methyl-4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) Preparation of Acrylamide

N- (3-((3-methyl-4-((4-morpholinophenyl) amino) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d ] Pyrimidin-6-yl) amino) phenyl) acrylamide (20 mg, 0.043 mmol) is added to methanol (0.5 mL), and hydrochloric acid (4 N, dioxane, 1 mL) is added, followed by 15 at room temperature. Stir for minutes. After completion of the reaction, the mixture is concentrated under reduced pressure to obtain a compound. (18 mg, 92%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52-7.50 (d, J = 8.85 Hz, 2H), 7.24-7.12 (m, 4H), 6.95-6.92 (d, J = 8.85), 6.47-6.41 (m , 1H), 6.29-6.26 (m, 1H), 5.93-5.89 (m, 1H), 3.89-3.86 (t, 4H), 3.17-3.14 (t, 4H)

Example 46 N- (3-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) Preparation of Phenyl) acrylamide

Step 1: N- (3-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) Step 1: N- (3-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- Preparation of 4-yl) amino) phenyl) acrylamide

4,6-dichloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (200 mg, 0.73 mmol in ethanol (1 mL) ), Trifluoric acetic acid (256 vL, 1.8 mmol) is added and stirred at room temperature for 14 hours. After the reaction was completed, the resultant was filtered to obtain the target compound. (175 mg, 58%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 2H), 7.31-7.30 (d, 1H), 7.19-7.14 (t, 2H), 7.07-7.04 (d, 1H), 6.43-6.37 (d , 1H), 6.24-6.15 (q, 1H), 5.86-5.83 (d, 1H), 5.74-5.71 (d, 1H), 4.15-4.13 (d, 1H), 3.80-3.76 (t, 1H), 2.57 (s, 3H), 2.05-2.04 (m, 2H), 1.89-1.76 (m, 4H).

Step 2: N- (3-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) Preparation of Acrylamide

Ethoxyethanol (0.08 M HCl, 2 mL) in N- (3-((6-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4 -d] pyrimidin-4-yl) amino) phenyl) acrylamide (42 mg, 0.10 mmol) and 4-morpholinoanili (19 mg, 0.10 mmol) are added, followed by stirring at 110 ^° C. for 14 hours. . After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous forget-me-not, filtered and concentrated. The concentrate was chromatographed to give the target compound. (17 mg, 35%)

¹ H NMR (300 MHz, MeOH) δ 8.05 (s, 1H), 7.51-7.48 (d, 3H), 7.38-7.30 (m, 3H), 6.83-6.81 (d, 2H), 6.42-6.38 (d, 2H), 5.77-5.75 (d, 1H), 3.79 (s, 4H), 3.02 (s, 4H), 2.61 (s, 3H).

Tables 1 and 2 summarize the chemical structures of the compounds prepared in Examples 1 to 46.

Example Chemical structure Example Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

Example Chemical structure Example Chemical structure 25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

Experimental Example 1 Evaluation of Bruton's tyrosine kinase (BTK) activity inhibition of conjugated pyrimidine derivatives

In order to evaluate the inhibition of Bruton's tyrosine kinase activity of the conjugated pyrimidine derivatives according to the present invention, the following experiment was performed and the results are shown in Table 3.

BTK enzyme evaluation was assessed using the BTK inhibitor assay kit (Ciesbio, Codolet, France). ATP (adenosine triphosphate), BTK, peptide (biotin-Aca-AAAEEIYGEI-NH2) and the compounds of Examples 1-34 according to the present invention were added, reacted for 30 minutes, and the reaction was stopped by adding ethylenediaminetetraacetic acid (EDTA) thereto. I was. The EDTA solution contains europium-containing antibody (antiphosphoresidue antibody) and straptavidin-XL665 (SA-XL665, cisbio), incubated for 1 hour, and measured for fluorescence. The value was determined by measuring the emission of 665 and 620 nm that were excited at 337 nm with a reader. IC ₅₀ values were obtained using GraphPad Prism (5 version). The curves are obtained from the logarithmic function and the response using a non-linear regression model.

Experimental Example 2 Evaluation of Inhibition of TMD80 Activity of Conjugated Pyrimidine Derivatives

In order to evaluate the inhibition of TMD80 activity of the conjugated pyrimidine derivatives according to the present invention, the following experiment was performed and the results are shown in Table 3.

TMD8 cells were divided into 96-well plates (about 30% solution) and treated with the active compounds. After 72 hours, the WST-1 reagent was added and the absorbance (450 nm) was measured. (Spectramax spectrometer, Molecular Devices, USA). IC ₅₀ values were obtained using GraphPad Prism (5 version). The curves are obtained from the logarithmic function and the response using a non-linear regression model.

Example Btk
IC ₅₀ (uM) TMD80
IC ₅₀ (uM) Example Btk
IC ₅₀ (uM) TMD80
IC ₅₀ (uM) One 0.46 1.2 24 0.035 10 2 0.048 1.5 25 10 2.2 3 1.1 2.5 26 0.21 0.23 4 1.7 10 27 0.092 0.76 5 0.0049 10 28 0.049 0.63 6 0.14 10 29 0.017 1.9 7 0.11 2.16 30 0.04 10 8 0.14 10 31 2.1 1.3 9 0.34 10 32 0.03 0.45 10 0.25 10 33 0.005 0.02482 11 0.21 0.01 34 2.5 2.8 12 0.017 0.07 35 10 4 13 0.17 10 36 10 10 14 0.008 0.18 37 0.005 0.01681 15 0.003 0.09 38 0.001 0.03213 16 0.03 0.14 39 0.001 0.1343 17 0.05 1.3 40 0.083 0.7965 18 0.01 5.06 41 0.008 0.1079 19 0.005 3.95 42 0.43 3.695 20 0.001 0.25 43 1.2 0.46 21 0.001 0.01 44 2.5 0.18 22 0.15 2 45 0.024 0.5672 23 1.5 1.7 46 0.0014 0.02258

As shown in Table 3, the conjugated pyrimidine derivatives according to the present invention inhibit the activity of Bruton's tyrosine kinase with IC ₅₀ values of 10 μM or less, Examples 3, 5, 12, 14-21, 24, 27 , 28, 30, 32, 33, 37-39, 41, 45 and 46 compounds exhibit a low IC ₅₀ value of 0.05 μM or less, i.e., 50 nM or less, indicating excellent Bruton's tyrosine kinase activity inhibition. In particular, Examples 14, 15, 19-21, 33, 37-39, and 41 compounds were found to inhibit Bruton's tyrosine kinase activity with significant IC ₅₀ values of 0.008 μM, ie 8 nM or less.

In addition, the conjugated pyrimidine derivatives according to the present invention inhibit the activity of TMD80 with IC ₅₀ values of 10 μM or less, and the compounds of Examples 11, 21, 27, 28 and 46 are 0.05 μM or less, i.e., low IC of 50 nM or less. _A value of ₅₀ was shown, indicating that excellent TMD80 activity was suppressed.

Therefore, the conjugated pyrimidine derivatives according to the present invention have excellent ability to inhibit the activity of Bruton's tyrosine kinase or TMD80, and thus can be usefully used for preventing or treating diseases related to Bruton's tyrosine kinase activity, especially cancer or autoimmune diseases. Can be.

Preparation Example 1 Preparation of Powder

2 g of a compound represented by Formula 1

1g lactose

The above ingredients were mixed and filled in airtight cloth to prepare a powder.

Preparation Example 2 Preparation of Tablet

100 mg of compound represented by formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

Preparation Example 3 Preparation of Capsule

100 mg of compound represented by formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

Preparation Example 4 Preparation of Injection

100 mg of compound represented by formula (1)

Mannitol 180 mg

Na ₂ HPO ₄ 2H ₂ O 26 mg

Distilled water 2974 mg

According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.

Preparation Example 5 Preparation of Health Food

500ng compound represented by formula (1)

Vitamin Mixture

Vitamin A Acetate 70mg

Vitamin E 1.0mg

0.13 mg of vitamin

Vitamin B2 0.15mg

Vitamin B6 0.5mg

Vitamin B12 0.2mg

Vitamin C 10mg

Biotin 10mg

Nicotinic Acid 1.7mg

Folic acid 50mg

Calcium Pantothenate 0.5mg

Mineral mixture

Ferrous Sulfate 1.75mg

Zinc Oxide 0.82mg

Magnesium carbonate 25.3mg

15 mg potassium monophosphate

Dicalcium Phosphate 55mg

Potassium Citrate 90mg

Calcium Carbonate 100mg

Magnesium chloride 24.8mg

Although the composition ratio of the vitamin and mineral mixture is a composition suitable for a relatively healthy food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.

Preparation Example 6 Preparation of Health Beverage

500ng compound represented by formula (1)

Citric acid 1000mg

Oligosaccharide 100g

Plum concentrate 2g

1 g of taurine

Add 900 ml of purified water

After mixing the above components in accordance with a conventional method for preparing a healthy beverage, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed sterilization and refrigerated and then stored in a healthy beverage composition Used for preparation.

Although the composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

Claims (14)

A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound is any one selected from the following compound group:
<1> 1- (4- (4-((6- (p-tolylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) piperazin-1-yl ) Ethan-1-one;
<2> 1- (4- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) pipe Razin-1-yl) ethan-1-one;
<3> (R) -N- (1- (6- (4-morpholinophenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidin-3-yl ) Acrylamide;
<4> (S) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine-3- I) acrylamide;
<5> 1- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- Yl) propen-2-en-1-one;
<6> 1- (4-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pi Ferridin-1-yl) propen-2-en-1-one;
<7> 4 (R) -N- (1- (6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperidine- 3-yl) acrylamide;
<8> (S) -1- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine- 4-yl) amino) piperidin-1-yl) prope-2-en-1-one;
<9> 1- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- I) propan-1-one;
<10> (S) -1- (3-((6-((4- (piperazin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) piperidin-1-yl) propen-2-en-1-one;
<11> 1- (4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidin-1-yl) prope -2-en-1-one;
<12> 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- Yl) propen-2-en-1-one;
<13> 1- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) piperidine-1- Yl) propen-2-en-1-one;
<14> N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylamide;
<15> N-((1s, 4s) -4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) Cyclohexyl) acrylamide;
<16> (R) -1- (3-((6-([1, 1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) pyrrolidin-1-yl) propen-2-en-1-one;
<17> (R) -1- (3-((6-([1, 1'-diphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Amino) pyrrolidin-1-yl) propen-2-en-1-one;
<18> (R) -1- (3-((6-((4-phenoxyphenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine -1-yl) propen-2-en-1-one;
<19> (R) -1- (3-((6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4- I) amino) pyrrolidin-1-yl) prope-2-en-1-one;
<20> N-((1s, 4s) -4-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidine-4- One) amino) cyclohexyl) acrylamide;
<21> N- (3-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
<22> N-((1s, 4s) -4-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) acrylic amides;
<23> N-((1s, 4s) -4-((6- (4-phenoxyphenoxy) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) cyclohexyl) Acrylamide;
<24> N-((1s, 4s) -4-((3-methyl-6-((4- (piperidin-1-yl) phenyl) amino) -1H-pyrazolo [3,4-d ] Pyrimidin-4-yl) amino) cyclohexyl) acrylamide;
<25> (R) -1- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) pyrrolidine-1- Yl) propen-2-en-1-one;
<26> N-((1s, 4s) -4-((6-([1, 1'-biphenyl] -4-ylamino) -1H-pyrazolo [3,4-d] pyrimidine-4 -Yl) amino) cyclohexyl) acrylamide;
<27> N-((1s, 4s) -4-((2-((4-morpholinophenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) Cyclohexyl) acrylamide;
N- (2-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
N- (4-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
N ^4, N ⁶ -bis (4-morpholinophenyl) -1H-pyrazolo [3,4-d] pyrimidine-4, 6-diamine;
N ^4- (3-aminophenyl) -N2- (4-morpholinophenyl) -7H-pyrrolo [2, 3-d] pyrimidine-2, 4-diamine;
N- (3-((4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) acrylamide;
N- (3-((2-((4-morpholinophenyl) amino) -9H-purin-6-yl) amino) phenyl) acrylamide;
N- (3-((2-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
N- (3-((4-((4-morpholinophenyl) amino) pyrido [2,3-d] pyrimidin-2-yl) amino) phenyl) acrylamide;
N ^2, N ⁴ -bis (4-morpholinophenyl) pyrido [2, 3-d] pyrimidine-2, 4-diamine;
<37> N- (3-((6-((4- (4-acetylpiperazin-1-yl) phenyl) amino) -3-methyl-1H-pyrazolo [3,4-d] pyrimidine- 4-yl) amino) phenyl) acrylamide;
N- (3-((6-((4- (1-methyl-5, 6-dihydro-1, 2, 4-triazin-4 (1H) -yl) phenyl) amino) -1H -Pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
1- (6-((6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) Prope-2-en-1-one;
<40> 1- (6-((2-((4-morpholinophenyl) amino) pyrido [2, 3-d] pyrimidin-4-yl) amino) indolin-1-yl) prope -2-en-1-one;
N- (3-((6-((3-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
N- (3-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) acrylamide;
<43> 1- (6-((6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl) prope- 2-en-1-one;
<44> 1- (6-((3-methyl-6- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) indolin-1-yl Prope-2-en-1-one;
<45> N- (3-((3-methyl-4-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-6-yl) amino) phenyl) Acrylamide; And
<46> N- (3-((3-methyl-6-((4-morpholinophenyl) amino) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) phenyl) Acrylamide.
delete delete delete As shown in Scheme 1 below,
Preparing a compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 4 (step 1); And
It is any one selected from the compound group of claim 1 comprising the step (step 2) of obtaining a compound represented by the formula (1) by reacting the compound represented by the formula (2) obtained in step 1 with the compound represented by the formula (5) Method for preparing the compound:
Scheme 1

(In Scheme 1,
n, A, D ^1, D ^2, D ^3, R ^1, R ^2, R ³ and

Is as defined in the compound name of claim 1;
X ¹ and X ² are each independently the same or different halogen; And
L ¹ is hydrogen,

or

to be).
As shown in Scheme 2 below,
Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 3 with the compound represented by Chemical Formula 5 (step 1); And
It is any one selected from the group of compounds of claim 1 comprising the step (step 2) of obtaining a compound represented by the formula (1) by reacting the compound represented by the formula (6) obtained in step 1 with the compound represented by the formula (4) Method for preparing the compound:
Scheme 2

(In Scheme 2,
n, A, D ^1, D ^2, D ^3, R ^1, R ^2, R ³ and

Is as defined in the compound name of claim 1;
X ¹ and X ² are each independently the same or different halogen; And
L ¹ is hydrogen,

or

to be).
A pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, which is any one selected from the group of compounds of claim 1.
The method of claim 7, wherein
The compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof is a pharmaceutical composition for preventing or treating cancer, characterized in that it inhibits the activity of Bruton's tyrosine kinase (BTK).
The method of claim 7, wherein
The cancer is a group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastases, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, fibrotic tumor and brain tumor A pharmaceutical composition for preventing or treating cancer, characterized in that any one selected from.
A pharmaceutical composition for the prophylaxis or treatment of autoimmune diseases, comprising as an active ingredient a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is any one selected from the group of compounds of claim 1.
The method of claim 10,
The compound, the optical isomer thereof or a pharmaceutically acceptable salt thereof is a pharmaceutical composition for preventing or treating autoimmune disease, characterized in that it inhibits the activity of Bruton's tyrosine kinase (BTK).
The method of claim 10,
The autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, hyperthyroidism, work sickness, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia and Sjogren's syndrome. Pharmaceutical composition for the prevention or treatment of autoimmune diseases, characterized in that any one.
A health functional food composition for preventing or ameliorating cancer comprising any one selected from the group of compounds of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A health functional food composition for preventing or ameliorating autoimmune diseases comprising any one selected from the group of compounds of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.